Does yoga therapy reduce blood pressure in patients with hypertension?: an integrative review.
The aim of this article was to present a evidence-based integrative research review that validates yoga therapy as an effective complementary treatment in the management of high blood pressure (BP). The article also uses the theoretical framework of Dr Hans Selye's general adaptation syndrome. Yoga researchers demonstrate that yoga works because it modulates the physiological system of the body, specifically its effect on the heart rate. This review is significant because yoga presents an effective method of treating hypertension that is nonpharmacologic and therefore there are no adverse effects and there are other valuable health benefits. Research suggests that stress is a contributing factor to high BP; hence, the use of the general adaptation syndrome and the most important attribute of yoga, that is, it is a physical and mental exercise program, that is in sync with the philosophy of holistic nursing care where one treats the whole individual and not just the disease. The review was conducted with a search of computerized databases such as OVID, Academic Search Premier, CINAHL, MEDLINE, and Health Source: Nursing/Academic edition, PsychINFO, as well as reliable Web sites such as the cdc.gov, among others. An integrative review search was conducted, and 10 studies met the inclusion criteria. They include a combination of randomized controlled trials, quasi-experimental studies, and pilot studies. Yoga therapy is a multifunctional exercise modality with numerous benefits. Not only does yoga reduce high BP but it has also been demonstrated to effectively reduce blood glucose level, cholesterol level, and body weight, major problems affecting the American society. The completed integrative review provides guidelines for nursing implementation as a complementary treatment of high BP.


Neuromuscular complications in the intensive care unit: critical illness polyneuromyopathy.
Critical illness polyneuromyopathy, a complication of critical illness, is a primary axonal degeneration of motor and sensory fibers that leads to skeletal muscle weakness. It significantly contributes to the unexplained difficulty in weaning from mechanical ventilation and to their prolonged rehabilitation and poor quality of life after discharge. This article will discuss the diagnosis of critical illness polyneuromyopathy, identify risk factors, review several pathomechanisms that have been proposed, and discuss the implications for practice.


TREECON: a software package for the construction and drawing of evolutionary trees.
A package of programs (run by a management program called TREECON) was developed for the construction and drawing of evolutionary trees. The program MATRIX calculates dissimilarity values and can perform boostrap analysis on nucleic acid sequences. TREE implements different evolutionary tree constructing methods based on distance matrices. Because some of these methods produce unrooted evolutionary trees, a program ROOT places a root on the tree. Finally, the program DRAW draws the evolutionary tree, changes its size or topology, and produces drawings suitable for publication. Whereas, MATRIX is suited only for nucleic acids, the modules TREE, ROOT and DRAW are applicable to any kind of dissimilarity matrix. The programs run on IBM-compatible microcomputers using the DOS operating system.


Effect of Cognitive Disability and Ambulation Status on Functioning in Moderate-to-Advanced Parkinson Disease.
Background: As the disease progresses to moderate to advanced stages, people with Parkinson's disease (PwP) are likely to have various degrees of disability due to the motor and non-motor symptoms, such as ambulatory difficulty and cognitive impairment. The objective of this study was to investigate the impact of cognition and ambulation status on the functioning and disability of PwP using the World Health Orgnaization Disability Assessment Schedule 2.0 (WHODAS 2.0). Materials and Methods: A group of 10,581 PwP with Hoehn and Yahr Staging 3 and above were collected from a database of disability evaluation and functional assessment using the Taiwan Data Bank of Persons with Disability between July 2012 and October 2018. WHODAS 2.0 was administered and all PwP were grouped based on their ambulatory status, which was assessed by 3-m back and forth walk and cognitive ability, assessed by WHODAS 2.0 first domain with cut-off level at 58. Results: Non-ambulation and cognitive disability contributed independently to disability in all aspects of WHODAS 2.0 survey, including self-care, getting along with others, performing life activities and participation in society. Compared to ambulation status, cognitive disability had a greater negative impact on functioning in all aspects. Conclusion: Cognitive disability was associated with greater disability in moderate to advanced PwP than non-ambulatory status. The results of this study may indicate that cognition preservation is essential to ameliorate functional impairment and disability in moderate to advanced PwP.


Morphologic, host specificity, and molecular characterization of a Hungarian Cryptosporidium meleagridis isolate.
This study was undertaken in order to characterize Cryptosporidium meleagridis isolated from a turkey in Hungary and to compare the morphologies, host specificities, organ locations, and small-subunit RNA (SSU rRNA) gene sequences of this organism and other Cryptosporidium species. The phenotypic differences between C. meleagridis and Cryptosporidium parvum Hungarian calf isolate (zoonotic genotype) oocysts were small, although they were statistically significant. Oocysts of C. meleagridis were successfully passaged in turkeys and were transmitted from turkeys to immunosuppressed mice and from mice to chickens. The location of C. meleagridis was the small intestine, like the location of C. parvum. A comparison of sequence data for the variable region of the SSU rRNA gene of C. meleagridis isolated from turkeys with other Cryptosporidium sequence data in the GenBank database revealed that the Hungarian C. meleagridis sequence is identical to a C. meleagridis sequence recently described for a North Carolina isolate. Thus, C. meleagridis is a distinct species that occurs worldwide and has a broad host range, like the C. parvum zoonotic strain (also called the calf or bovine strain) and Cryptosporidium felis. Because birds are susceptible to C. meleagridis and to some zoonotic strains of C. parvum, these animals may play an active role in contamination of surface waters not only with Cryptosporidium baileyi but also with C. parvum-like parasites.


Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.
Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.


Self-protective biases in group categorization: threat cues shape the psychological boundary between "us" and "them".
Across 6 studies, factors signaling potential vulnerability to harm produced a bias toward outgroup categorization--a tendency to categorize unfamiliar others as members of an outgroup rather than as members of one's ingroup. Studies 1 through 4 demonstrated that White participants were more likely to categorize targets as Black (as opposed to White) when those targets displayed cues heuristically associated with threat (masculinity, movement toward the perceiver, and facial expressions of anger). In Study 5, White participants who felt chronically vulnerable to interpersonal threats responded to a fear manipulation by categorizing threatening (angry) faces as Black rather than White. Study 6 extended these findings to a minimal group paradigm, in which participants who felt chronically vulnerable to interpersonal threats categorized threatening (masculine) targets as outgroup members. Together, findings indicate that ecologically relevant threat cues within both the target and the perceiver interact to bias the way people initially parse the social world into ingroup vs. outgroup. Findings support a threat-based framework for intergroup psychology.


Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1.
Synaptotagmin 1 likely acts as a Ca2+ sensor in neurotransmitter release by Ca2+-binding to its two C2 domains. This notion was strongly supported by the observation that a mutation in the C2A domain causes parallel decreases in the apparent Ca2+ affinity of synaptotagmin 1 and in the Ca2+ sensitivity of release. However, this study was based on a single loss-of-function mutation. We now show that tryptophan substitutions in the synaptotagmin 1 C2 domains act as gain-of-function mutations to increase the apparent Ca2+ affinity of synaptotagmin 1. The same substitutions, when introduced into synaptotagmin 1 expressed in neurons, enhance the Ca2+ sensitivity of release. Mutations in the two C2 domains lead to comparable and additive effects in release. Our results thus show that the apparent Ca2+ sensitivity of release is dictated by the apparent Ca2+ affinity of synaptotagmin 1 in both directions, and that Ca2+ binding to both C2 domains contributes to Ca2+ triggering of release.


Counselling and management of cardiovascular risk factors after preeclampsia.
Women with a history of preeclampsia have an increased risk of cardiovascular disease. Gynaecologists have an important role in the counselling and management of cardiovascular risk factors after preeclampsia. We aimed to assess the role of gynaecologists in informing women on interventions and risk factor follow-up after early and late preeclampsia. In 2011 and 2014, all gynaecologists in the Netherlands were invited for a questionnaire. Results were analysed and compared over time. In 2011, the questionnaire was answered by 244 and in 2014 by 167 gynaecologists. After early preeclampsia, in 2011, 53% advised yearly blood pressure measurements; this increased to 65% in 2014. Over the years there was an increase in respondents advising an increased physical activity of 35% in 2011 to 56% in 2014. After late preeclampsia, in 2011, 36% advised yearly blood pressure measurements; this increased to 46% in 2014. There was an increase in gynaecologists advising increased activity (32% in 2011 to 56% in 2014). In both early and late preeclampsia, smoking cessation and weigh loss were advised often (70-80%); glucose and lipid screening were advised rarely (6-20%). Although there is still a considerable scope for improvement, an increasing number of gynaecologists advise women after preeclampsia on preventive interventions to decrease risks of cardiovascular disease.


The effect of neural adaptation on population coding accuracy.
Most neurons in the primary visual cortex initially respond vigorously when a preferred stimulus is presented, but adapt as stimulation continues. The functional consequences of adaptation are unclear. Typically a reduction of firing rate would reduce single neuron accuracy as less spikes are available for decoding, but it has been suggested that on the population level, adaptation increases coding accuracy. This question requires careful analysis as adaptation not only changes the firing rates of neurons, but also the neural variability and correlations between neurons, which affect coding accuracy as well. We calculate the coding accuracy using a computational model that implements two forms of adaptation: spike frequency adaptation and synaptic adaptation in the form of short-term synaptic plasticity. We find that the net effect of adaptation is subtle and heterogeneous. Depending on adaptation mechanism and test stimulus, adaptation can either increase or decrease coding accuracy. We discuss the neurophysiological and psychophysical implications of the findings and relate it to published experimental data.


Gene therapy imaging in patients for oncological applications.
Thus far, traditional methods for evaluating gene transfer and expression have been shown to be of limited value in the clinical arena. Consequently there is a real need to develop new methods that could be repeatedly and safely performed in patients for such purposes. Molecular imaging techniques for gene expression monitoring have been developed and successfully used in animal models, but their sensitivity and reproducibility need to be tested and validated in human studies. In this review, we present the current status of gene therapy-based anticancer strategies and show how molecular imaging, and more specifically radionuclide-based approaches, can be used in gene therapy procedures for oncological applications in humans. The basis of gene expression imaging is described and specific uses of these non-invasive procedures for gene therapy monitoring illustrated. Molecular imaging of transgene expression in humans and evaluation of response to gene-based therapeutic procedures are considered. The advantages of molecular imaging for whole-body monitoring of transgene expression as a way to permit measurement of important parameters in both target and non-target organs are also analyzed. The relevance of this technology for evaluation of the necessary vector dose and how it can be used to improve vector design are also examined. Finally, the advantages of designing a gene therapy-based clinical trial with imaging fully integrated from the very beginning are discussed and future perspectives for the development of these applications outlined.


CRISPR therapeutic tools for complex genetic disorders and cancer (Review).
One of the fundamental discoveries in the field of biology is the ability to modulate the genome and to monitor the functional outputs derived from genomic alterations. In order to unravel new therapeutic options, scientists had initially focused on inducing genetic alterations in primary cells, in established cancer cell lines and mouse models using either RNA interference or cDNA overexpression or various programmable nucleases [zinc finger nucleases (ZNF), transcription activator-like effector nucleases (TALEN)]. Even though a huge volume of data was produced, its use was neither cheap nor accurate. Therefore, the clustered regularly interspaced short palindromic repeats (CRISPR) system was evidenced to be the next step in genome engineering tools. CRISPR-associated protein 9 (Cas9)-mediated genetic perturbation is simple, precise and highly efficient, empowering researchers to apply this method to immortalized cancerous cell lines, primary cells derived from mouse and human origins, xenografts, induced pluripotent stem cells, organoid cultures, as well as the generation of genetically engineered animal models. In this review, we assess the development of the CRISPR system and its therapeutic applications to a wide range of complex diseases (particularly distinct tumors), aiming at personalized therapy. Special emphasis is given to organoids and CRISPR screens in the design of innovative therapeutic approaches. Overall, the CRISPR system is regarded as an eminent genome engineering tool in therapeutics. We envision a new era in cancer biology during which the CRISPR-based genome engineering toolbox will serve as the fundamental conduit between the bench and the bedside; nonetheless, certain obstacles need to be addressed, such as the eradication of side-effects, maximization of efficiency, the assurance of delivery and the elimination of immunogenicity.


A cobalt phosphide catalyst for the hydrogenation of nitriles.
The study of metal phosphide catalysts for organic synthesis is rare. We present, for the first time, a well-defined nano-cobalt phosphide (nano-Co2P) that can serve as a new class of catalysts for the hydrogenation of nitriles to primary amines. While earth-abundant metal catalysts for nitrile hydrogenation generally suffer from air-instability (pyrophoricity), low activity and the need for harsh reaction conditions, nano-Co2P shows both air-stability and remarkably high activity for the hydrogenation of valeronitrile with an excellent turnover number exceeding 58000, which is over 20- to 500-fold greater than that of those previously reported. Moreover, nano-Co2P efficiently promotes the hydrogenation of a wide range of nitriles, which include di- and tetra-nitriles, to the corresponding primary amines even under just 1 bar of H2 pressure, far milder than the conventional reaction conditions. Detailed spectroscopic studies reveal that the high performance of nano-Co2P is attributed to its air-stable metallic nature and the increase of the d-electron density of Co near the Fermi level by the phosphidation of Co, which thus leads to the accelerated activation of both nitrile and H2. Such a phosphidation provides a promising method for the design of an advanced catalyst with high activity and stability in highly efficient and environmentally benign hydrogenations.


Planning activity for internally generated reward goals in monkey amygdala neurons.
The best rewards are often distant and can only be achieved by planning and decision-making over several steps. We designed a multi-step choice task in which monkeys followed internal plans to save rewards toward self-defined goals. During this self-controlled behavior, amygdala neurons showed future-oriented activity that reflected the animal's plan to obtain specific rewards several trials ahead. This prospective activity encoded crucial components of the animal's plan, including value and length of the planned choice sequence. It began on initial trials when a plan would be formed, reappeared step by step until reward receipt, and readily updated with a new sequence. It predicted performance, including errors, and typically disappeared during instructed behavior. Such prospective activity could underlie the formation and pursuit of internal plans characteristic of goal-directed behavior. The existence of neuronal planning activity in the amygdala suggests that this structure is important in guiding behavior toward internally generated, distant goals.


Percutaneous Treatment of Coronary Chronic Total Occlusions Part 1: Rationale and Outcomes.
Coronary chronic total occlusions (CTOs) are commonly encountered in patients with coronary artery disease. Compared to patients without coronary CTOs, those with CTO have worse clinical outcomes and lower likelihood of complete coronary revascularisation. Successful CTO percutaneous coronary intervention (PCI) can significantly improve angina and improve left ventricular function. Although currently unproven, successful CTO PCI might also reduce the risk for arrhythmic events in patients with ischaemic cardiomyopathy, provide better tolerance of future acute coronary syndrome, and possibly improve survival. Evaluation by a heart team comprised of both interventional and non-interventional cardiologists and cardiac surgeons is important for determining the optimal revascularisation strategy in patients with coronary artery disease and CTOs. Ad hoc CTO PCI is generally not recommended, so as to allow sufficient time for (a) discussion with the patient about the indications, goals, risks, and alternatives to PCI; (b) careful procedural planning; and (c) contrast and radiation exposure minimisation. Use of drug-eluting stents is recommended for CTO PCI, given the lower rates of angiographic restenosis compared to bare metal stents.


Older adults with non-communicable chronic conditions and their health care access amid COVID-19 pandemic in Bangladesh: Findings from a cross-sectional study.
Burgeoning burden of non-communicable disease among older adults is one of the emerging public health problems. In the COVID-19 pandemic, health services in low- and middle-income countries, including Bangladesh, have been disrupted. This may have posed challenges for older adults with non-communicable chronic conditions in accessing essential health care services in the current pandemic. The present study aimed at exploring the challenges experienced by older Bangladeshi adults with non-communicable chronic conditions in receiving regular health care services during the COVID-19 pandemic. The study followed a cross-sectional design and was conducted among 1032 Bangladeshi older adults aged 60 years and above during October 2020 through telephone interviews. Self-reported information on nine non-communicable chronic conditions (osteoarthritis, hypertension, heart disease, stroke, hypercholesterolemia, diabetes, chronic respiratory diseases, chronic kidney disease, cancer) was collected. Participants were asked if they faced any difficulties in accessing medicine and receiving routine medical care for their medical conditions during the COVID-19 pandemic. The association between non-communicable chronic conditions and accessing medication and health care was analysed using binary logic regression model. Most of the participants aged 60-69 years (77.8%), male (65.5%), married (81.4%), had no formal schooling (58.3%) and resided in rural areas (73.9%). Although more than half of the participants (58.9%) reported having a single condition, nearly one-quarter (22.9%) had multimorbidity. About a quarter of the participants reported difficulties accessing medicine (23%) and receiving routine medical care (27%) during the pandemic, and this was significantly higher among those suffering from multimorbidity. In the adjusted analyses, participants with at least one condition (AOR: 1.95, 95% CI: 1.33-2.85) and with multimorbidity (AOR: 4.75, 95% CI: 3.17-7.10) had a higher likelihood of experiencing difficulties accessing medicine. Similarly, participants with at least one condition (AOR: 3.08, 95% CI: 2.11-4.89) and with multimorbidity (AOR: 6.34, 95% CI: 4.03-9.05) were significantly more likely to face difficulties receiving routine medical care during the COVID-19 pandemic. Our study found that a sizeable proportion of the older adults had difficulties in accessing medicine and receiving routine medical care during the pandemic. The study findings highlight the need to develop an appropriate health care delivery pathway and strategies to maintain essential health services during any emergencies and beyond. We also argue the need to prioritise the health of older adults with non-communicable chronic conditions in the centre of any emergency response plan and policies of Bangladesh.


Collective motion of cells modeled as ring polymers.
In this article, we use a coarse-grained model of disjoint semi-flexible ring polymers to investigate computationally the spatiotemporal collective behavior of cell colonies. A ring polymer in this model is self-propelled by a motility force along the cell's polarity, which depends on its historical kinetics. Despite the repulsive interaction between the cells, a collective behavior sets in as a result of cells pushing against each other. This cooperative motion emerges as the amplitude of the motility force is increased and/or their areal density is increased. The degree of collectivity, characterized by the average cluster size, the velocity field order parameter, and the polarity field nematic order parameter, is found to increase with increasing the amplitude of the motility force and area coverage of the cells. Furthermore, the degree of alignment exhibited by the cell velocity field within a cluster is found to be stronger than that exhibited by the cell polarity. Comparison between the collective behavior of elongated cells and that of circular cells, at the same area coverage and motility force, shows that elongated cells exhibit a stronger collective behavior than circular cells, in agreement with earlier studies of self-propelled anisotropic particles. An investigation of two-cell collisions shows that while two clustered cells move in tandem, their polarities are misaligned. As such the cells push against each other while moving coherently.


Attachment of Vibrio alginolyticus to chitin mediated by chitin-binding proteins.
Vibrio alginolyticus is the only culturable vibrio associated with the chitinaceous carapace of the copepod Tigriopus fulvus (Fisher 1860) living in Ligurian coastal rock pools (Tyrrhenian Sea). The characteristics of the interaction between chitin particles and V. alginolyticus were studied by analysing strains isolated both from the copepod surface and from rock-pool water. The highest degree of attachment to chitin was observed at 20 degrees C, in the presence of 3% NaCl. Bacterial treatment with N-acetylglucosamine and pronase E caused a reduction in attachment of 52-62% and 77-94%, respectively. Chitin pretreatment with either wheat germ agglutinin or membrane proteins (MPs) from V. alginolyticus caused a reduction in attachment, of 50-57% and 53-70%, respectively. No inhibition was observed when bacteria were pretreated with D-glucose, D-fucose or D-fructose, or when chitin was pretreated with concanavalin A and Escherichia coli DH5 alpha MPs. V. alginolyticus MPs able to bind chitin were isolated and analysed by SDS-PAGE. Four chitin-binding proteins were visualized in all tested strains (53, 35, 20 and 14 kDa); in vivo these peptides may efficiently mediate V. alginolyticus attachment to chitin-containing substrates.


Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids.
The use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB1/2-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.


Polymerase chain reaction diagnosis of Helicobacter pylori in gastroduodenal diseases: comparison with culture and histopathological examinations.
Helicobacter pylori has been associated with a variety of upper gastrointestinal diseases. Histopathological examination and culture are considered to be the more specific tests in the diagnosis of H. pylori infection. In the present study, we evaluated the efficiency of a polymerase chain reaction (PCR) assay of the H. pylori urease A gene as a procedure in the diagnosis of gastric H. pylori infection in various gastroduodenal diseases. Biopsy specimens were obtained from the antral mucosa of 83 patients during endoscopic examination and were submitted to three tests for the detection of H. pylori infection. The detection rates of H. pylori using PCR, histopathological examination and culture were 84, 77 and 63%, respectively. When the infection was defined, by the agreement of culture and histopathological examination or by positive culture, the PCR assay had a sensitivity of 98.1% and a specificity of 84.6%. When the infection was defined by a positive result of either two of the three tests or by positive culture, the PCR assay had a sensitivity of 98.6% and a specificity of 85.7%. We conclude that the PCR assay is a valuable test for the diagnosis of H. pylori infection in gastroduodenal diseases.


Compassionate versus consequentialist conservation.
Ethical treatment of wildlife and consideration of animal welfare have become important themes in conservation, but ethical perspectives on how best to protect wild animals and promote their welfare are diverse. There are advantages to the consequentialist harms ethical framework applied in managing wild herbivores for conservation purposes. To minimize harms while achieving conservation goals, we argue that overabundant wild herbivores should in many cases be managed through consumptive in situ killing. Advantages of this policy are that the negative welfare states imposed on animals last only a short time; remaining animals are not deprived of positive welfare states (e.g., linked to rearing offspring); poor welfare states of animals in overabundant populations are avoided (e.g., starvation); negative welfare impacts on heterospecifics through resource depletion (i.e., competition) are prevented; harvesting meat reduces the number of (agricultural) animals raised to supply meat; and minimal costs maximize funding for other wildlife management and conservation priorities. Alternative ethical approaches to our consequentialist framework include deontology (containing animal rights) and virtue ethics, some of which underpin compassionate conservation. These alternative ethical approaches emphasize the importance of avoiding intentional killing of animals but, if no population reduction occurs, are likely to impose considerable unintentional harms on overabundant wildlife and indirectly harm heterospecifics through ineffective population reduction. If nonlethal control is used, it is likely that overabundant animals would be deprived of positive welfare states and economic costs would be prohibitive. We encourage conservation stakeholders to consider animal-welfare consequentialism as an ethical approach to minimize harms to the animals under their care as well as other animals that policies may affect while at the same time pursuing conservation goals.


[Pharmacological update in attention deficit hyperactivity disorder: models of intervention and new drugs].
INTRODUCTION. Attention deficit hyperactivity disorder (ADHD) is the most frequent neurodevelopmental problem in childhood, with significant repercussions that continue into adulthood. This means that an appropriate therapeutic intervention is vital to improve its prognosis. AIMS. To identify the ideal pharmacological options according to the characteristics of the patient and to report on the new drugs. DEVELOPMENT. The work analyses how therapeutic interventions can be conditioned by the anatomical substrate of the brain, the biochemical bases, genetics, neurophysiological examinations, neuropsychological studies and the clinical symptoms and subtypes. A significant amount of importance is granted to neuropsychological studies, especially those dealing with the executive functions, including evaluation of attention, impulse control, and interference and cognitive flexibility. Taking into consideration the signal-to-noise characteristics can be useful when it comes to choosing the drug. CONCLUSIONS. The development of the pharmacological therapeutic options in ADHD opens up expectations concerning applicability and greater specificity in daily practice to fit the characteristics of each patient. Psychoeducation must always be included and a thorough study of each particular child is recommended. This should involve analysing the neuropsychological features of his or her brain function in order to be able to reflect on the ideal pharmacological option that allows more favourable progress.


Clinical correlations and genetic associations of metabolic syndrome in the United Arab Emirates.
Metabolic syndrome (MetS) contributes to increased risk of morbidity and mortality. The United Arab Emirates (UAE) has a high prevalence of MetS which may be linked to modifiable and genetic risk factors in the local population. The association between MetS as a phenotype and key genetic variants in the UAE has not been investigated. This study reports on the clinical, biochemical and genetic associations of MetS and its risk factors to improve individualized medicine outcomes. There were 471 subjects included in this cross-sectional study, 367 with MetS and 104 without MetS. Along with clinical and laboratory parameters, multiple risk genetic variants were tested for their association with MetS, which include 49 variants that have previously been shown to be linked with MetS development as a phenotype, 116 variants for association with waist-hip ratio (WHR), 398 variants with body-mass index (BMI), 213 variants with T2DM and insulin resistance, 307 variants with different lipid traits, 308 variants with blood pressure traits, and 64 variants with coronary and cerebrovascular accidents. Patients with MetS had higher rates of type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia (p < 0.0001). Waist circumference and T2DM were identified as the key risk factors for MetS development. Individuals with MetS were also found to have a higher rate of clinical complications than those without MetS (76% vs. 52%). Several gene variants including those of the FTO gene were found to be associated with a predisposition to developing MetS or some of its components (PFTO ~0.005-0.009). This study showed associations between MetS as well as clinical factors contributing to MetS and specific genetic and metabolic risk factors, providing an insight into the metabolic and genetic links to disease development. Knowledge with respect to population specific risk markers including at risk genotypes will help in early identification of individuals with increased susceptibility to MetS in the UAE and provide the opportunity for timely intervention to prevent or delay the onset of MetS.


Tumour risk associated with use of cellular telephones or cordless desktop telephones.
The use of cellular and cordless telephones has increased dramatically during the last decade. There is concern of health problems such as malignant diseases due to microwave exposure during the use of these devices. The brain is the main target organ. Since the second part of the 1990's we have performed six case-control studies on this topic encompassing use of both cellular and cordless phones as well as other exposures. Three of the studies concerned brain tumours, one salivary gland tumours, one non-Hodgkin lymphoma (NHL) and one testicular cancer. Exposure was assessed by self-administered questionnaires. Regarding acoustic neuroma analogue cellular phones yielded odds ratio (OR) = 2.9, 95 % confidence interval (CI) = 2.0-4.3, digital cellular phones OR = 1.5, 95 % CI = 1.1-2.1 and cordless phones OR = 1.5, 95 % CI = 1.04-2.0. The corresponding results were for astrocytoma grade III-IV OR = 1.7, 95 % CI = 1.3-2.3; OR = 1.5, 95 % CI = 1.2-1.9 and OR = 1.5, 95 % CI = 1.1-1.9, respectively. The ORs increased with latency period with highest estimates using > 10 years time period from first use of these phone types. Lower ORs were calculated for astrocytoma grade I-II. No association was found with salivary gland tumours, NHL or testicular cancer although an association with NHL of T-cell type could not be ruled out. We found for all studied phone types an increased risk for brain tumours, mainly acoustic neuroma and malignant brain tumours. OR increased with latency period, especially for astrocytoma grade III-IV. No consistent pattern of an increased risk was found for salivary gland tumours, NHL, or testicular cancer.


Effect of low recumbent angle on cycling performance, fatigue, and V˙O(2) kinetics.
This study aimed to examine the effect of the degree of inclination from upright to supine postures on cycling performance, fatigue, and oxygen uptake (V˙O(2)) kinetics. In experiment 1, 10 subjects performed graded and fatigue (exhaustive constant-load heavy exercise with 10 s all-out efforts interspersed every minute) tests at four cycling postures: upright, 30° recumbent (R), 15° R, and supine. In experiment 2, nine different subjects performed two bouts of constant-load heavy exercise in the same four cycling postures. Bout 1 was brought to failure, and bout 2 was limited to 6 min, so that the breath-by-breath V˙O(2) data from the first 6 min of each bout were averaged and curve fit. The time sustained during the graded test was significantly shorter in the supine compared with the other three postures and also shorter in the 15° R compared with the upright. The rate of fatigue was higher in the supine compared with the other three postures, and the normalized EMG activities of three leg muscles at end exercise were larger in the supine (and in some cases 15° R) compared with upright posture. The time sustained (min) during high-intensity constant-load cycling was significantly longer during upright (12.8 ± 5.3) and 30° R (14.2 ± 6.1) compared with 15° R (8.5 ± 1.7) and supine (6.8 ± 2.0) postures, but the amplitudes of the slow component of the V˙O(2) response (L·min) were larger during 15° R (0.57 ± 0.10) and supine (0.61 ± 0.15) compared with 30° R (0.39 ± 0.12) and also larger in the supine than upright (0.43 ± 0.13) postures. Inert gas rebreathing analysis revealed similar cardiac output responses at 60 s into the exercise among postures. Lowering the recumbent angle to 15° resulted in shorter performance, larger fatigue, and altered V˙O(2) kinetics.


The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.
Triple A syndrome is a human autosomal recessive disorder characterized by an unusual array of tissue-specific defects. Triple A syndrome arises from mutations in a WD-repeat protein of unknown function called ALADIN (also termed Adracalin or AAAS). We showed previously that ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport. Here, we present evidence indicating that NPC targeting is essential for the function of ALADIN. Characterization of mutant ALADIN proteins from triple A patients revealed a striking effect of these mutations on NPC targeting. A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm. Microscopic analysis of cells from a triple A patient revealed no morphological abnormalities of the nuclei, nuclear envelopes, or NPCs. Importantly, these findings indicate that defects in NPC function, rather than structure, give rise to triple A syndrome. We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues. Our findings provide a foundation for understanding the molecular basis of triple A syndrome and may lead to unique insights into the role of nucleocytoplasmic transport in adrenal function and neurodevelopment.


Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury.
The effect of CNS-targeted IL-6 gene expression has been thoroughly investigated in the otherwise nonperturbed brain but not following brain injury. Here we examined the impact of astrocyte-targeted IL-6 production in a traumatic brain injury (cryolesion) model using GFAP-IL6 transgenic mice. This study demonstrated that transgenic IL-6 production significantly increased wound healing following the cryolesion. Thus, at 20 days postlesion (dpl) the GFAP-IL6 mice showed almost complete wound healing compared to litter mate nontransgenic controls. It seems likely that a reduced inflammatory response in the long term could be responsible for this IL-6-related effect. Thus, while in the acute phase following cryolesion (1-6 dpl) the recruitment of macrophages and T lymphocytes was higher in GFAP-IL6 mice, at 10-20 dpl it was significantly reduced compared to controls. Reactive astrogliosis was also significantly increased up to but not including 20 dpl in the GFAP-IL6 mice. Oxidative stress as well as apoptotic cell death was significantly decreased throughout the time period studied in the GFAP-IL6 mice compared to controls. This could be linked to the altered inflammatory response as well as to the transgenic IL-6-induced increase of the antioxidant, neuroprotective proteins metallothionein-I + II. These results indicate that although in the brain the chronic astrocyte-targeted expression of IL-6 spontaneously induces an inflammatory response causing significant damage, during an acute neuropathological insult such as following traumatic injury, a clear neuroprotective role is evident.


American Society of Clinical Oncology clinical practice guidelines: opportunities and challenges.
The American Society of Clinical Oncology (ASCO) published its first clinical practice guideline, which focused on the use of hematopoietic colony-stimulating factors, in 1994. Since then, ASCO has published 24 additional guidelines or technology assessments on a range of topics and is developing 11 additional guidelines. Guidelines are among ASCO's most valued products, according to membership surveys and data from the JCO.org Web site. However, the same data from ASCO members have highlighted a number of limitations to the guideline program. These relate to the timelines of guideline updates, difficulties locating guidelines and related products, and challenges to implementing ASCO guidelines in everyday clinical practice. This article outlines the concrete steps that the ASCO Health Services Committee (HSC) is taking to address these limitations, including the institution of a more aggressive guideline updating schedule, a transition from narrative to systematic literature reviews to support the practice recommendations, a new Board of Directors-approved policy to permit endorsement of other groups' guidelines, and a robust Clinical Tools and Resources program that offers a range of guideline dissemination and implementation aids. Additional work is underway to establish stronger and deeper collaborations with practicing oncologists to expand their role in the review, field testing, and implementation of guideline clinical tools and resources. Finally, the HSC is discussing evaluation of the guidelines program to maximize the impact of ASCO clinical practice guidelines on clinical decision making and, ultimately, the quality of cancer care.


Combined Yb/Nd driver for optical parametric chirped pulse amplifiers.
We report on the developed front-end/pump system for optical parametric chirped pulse amplifiers. The system is based on a dual output fiber oscillator/power amplifier which seeds and assures all-optical synchronization of femtosecond Yb and picosecond Nd laser amplifiers operating at a central wavelength of 1030 nm and 1064 nm, respectively. At the central wavelength of 1030 nm, the fiber oscillator generates partially stretched 4 ps pulses with the spectrum supporting a <120 fs pulse duration and pulse energy of 0.45 nJ. The energy of generated 1064 nm pulses is 0.15 nJ, which is sufficient for the efficient seeding of high-contrast Nd:YVO chirped pulse regenerative amplifier/post amplifier systems generating 9 mJ pulses compressible to 16 ps duration. The power amplification stages, based on Nd:YAG crystals, provide 62 mJ pulses compressible to 20 ps pulse duration at a repetition rate of 1 kHz. Further energy scaling currently is prevented by limited dimensions of the diffraction gratings, which, because of the fast progress in MLD grating manufacturing technologies is only a temporary obstacle.


Assessment of relatedness between neurocan gene as bipolar disorder susceptibility locus and schizophrenia.
Large scale genetic association meta-analyses showed that neurocan (NCAN) gene polymorphism rs1064395 is susceptibility locus for bipolar disorder. These studies also included patients with bipolar disorder originated from Bosnia and Herzegovina. Followed by theory of shared genetic elements between bipolar disorder and schizophrenia susceptibility, other studies explored several genetic factors with schizophrenia vulnerability as well. In this work, authors investigated the association between previously confirmed bipolar disorder genetic risk factor- neurocan with schizophrenia in a population sample of Bosnia and Herzegovina. Ethical aspects of this research were assessed by Ethics Committee of Clinical Center University of Sarajevo. Blood samples for DNA extraction were taken from the total of 86 patients and healthy individuals who previously signed informed consent. Genotyping for rs 1064395 was done using direct sequencing method. A case-control analysis of common genetic polymorphism within neurocan gene and schizophrenia status in a consecutively sampled patient cohort have been done using Fisher-exact test with odds-ratio calculation. No statistically significant allele and genotype association with disease status was found (p>0.05). Our finding supports the fact that large-scale genetic association studies approach need to be employed when detecting the variants with small additive effect in phenotypes with complex ethiology.


Real-time effects of PEEP and tidal volume on regional ventilation and perfusion in experimental lung injury.
Real-time bedside information on regional ventilation and perfusion during mechanical ventilation (MV) may help to elucidate the physiological and pathophysiological effects of MV settings in healthy and injured lungs. We aimed to study the effects of positive end-expiratory pressure (PEEP) and tidal volume (VT) on the distributions of regional ventilation and perfusion by electrical impedance tomography (EIT) in healthy and injured lungs. One-hit acute lung injury model was established in 6 piglets by repeated lung lavages (injured group). Four ventilated piglets served as the control group. A randomized sequence of any possible combination of three VT (7, 10, and 15 ml/kg) and four levels of PEEP (5, 8, 10, and 12 cmH2O) was performed in all animals. Ventilation and perfusion distributions were computed by EIT within three regions-of-interest (ROIs): nondependent, middle, dependent. A mixed design with one between-subjects factor (group: intervention or control), and two within-subjects factors (PEEP and VT) was used, with a three-way mixed analysis of variance (ANOVA). Two-way interactions between PEEP and group, and VT and group, were observed for the dependent ROI (p = 0.035 and 0.012, respectively), indicating that the increase in the dependent ROI ventilation was greater at higher PEEP and VT in the injured group than in the control group. A two-way interaction between PEEP and VT was observed for perfusion distribution in each ROI: nondependent (p = 0.030), middle (p = 0.006), and dependent (p = 0.001); no interaction was observed between injured and control groups. Large PEEP and VT levels were associated with greater pulmonary ventilation of the dependent lung region in experimental lung injury, whereas they affected pulmonary perfusion of all lung regions both in the control and in the experimental lung injury groups.


Infusing informatics into interprofessional education: the iTEAM (Interprofessional Technology Enhanced Advanced practice Model) project.
The iTEAM goal is to prepare advanced practice nurses, physicians and pharmacists with the interprofessional (IP) core competencies (informatics, patient centric, quality-focused, evidence based care) to provide technology enhanced collaborative care by: offering technology enhanced learning opportunities through a required informatics course, advanced practice courses (team based experiences with both standardized and virtual patients) and team based clinical experiences including e-health experiences. The innovative features of iTEAM project will be achieved through use of social media strategies, a web accessible Electronic Health Records (EHRs) system, a Virtual Clinic/Hospital in Second Life, various e-health applications including traditional telehealth tools and consumer oriented tools such as patient portals, social media consumer groups and mobile health (m-health) applications for health and wellness functions. It builds upon the schools' rich history of IP education and includes clinical partners, such as the VA and other clinical sites focused on care for underserved patient populations.


The relation between mirror movements and non-use of the affected hand in children with unilateral cerebral palsy.
In children with unilateral cerebral palsy (CP), it is widely believed that mirror movements contribute to non-use of the affected hand despite preserved capacity, a phenomenon referred to as developmental disregard. We aimed to test whether mirror movements are related to developmental disregard, and to clarify the relation between mirror movements and bimanual function. A repetitive squeezing task simultaneously measuring both hands' grip-forces was developed to assess mirror movements by using maximum cross-correlation coefficient (CCCmax ) as well as strength measures (MMstrength ). Developmental disregard, bimanual performance, and capacity were assessed using a validated video-observation method. Twenty-one children with unilateral CP participated (Median age 10y 7mo, interquartile range [IQR] 10y 1mo-12y 9mo). Outcome measures of mirror movements were correlated to developmental disregard, bimanual performance, and capacity scores using Spearman's correlations (significance level: α<0.05). Mirror movements were not related to developmental disregard. However, enhanced mirror movements in the less-affected hand were related to reduced performance (CCCmax : ρ=-0.526, p=0.007; MMstrength : ρ=-0.750, p<0.001) and capacity (CCCmax : ρ=-0.410, p=0.033; MMstrength : ρ=-0.679, p<0.001). These relations were only moderate (performance:MMstrength : ρ=-0.504, p=0.010), low (capacity: MMstrength : ρ=-0.470, p=0.016) or absent for mirror movements in the affected hand. Additionally, seven children showed stronger movements in their less-affected hands when actually being asked to move their affected hand. These findings show no relation between mirror movements and developmental disregard, but support an association between mirror movements and bimanual function.


Pycnogenol® improvements in asthma management.
The simplification of the management of asthma in the different clinical phases of this common chronic inflammatory disorder is the main goal of therapy. Pycnogenol®, a standardized extract of French maritime pine bark, inhibits expression of 5-lipoxygenase and consequently decreases leukotriene levels in asthmatic patients. Pycnogenol® anti-inflammatory activities may be supportive when taken in addition to inhalation corticosteroid (ICS), putatively allowing for a reduction in dosage and frequency of ICS administration. This study evaluated the efficacy of Pycnogenol® during a period of six months for improving allergic (mite in house dust) asthma management in patients with stable, controlled conditions. Pycnogenol® was used at a daily dosage of 100 mg, distributed as 50 mg in the morning at 9 am and again in the evening at 9 pm). An individual patient's asthma condition was graded in five steps based on the daily dosage of inhaled fluticasone propionate with step 1 indicating 0 µg and step 5 the maximum dose of 500 µg ICS twice daily. A total 76 patients were enrolled for this study. The group taking Pycnogenol® in addition to ICS and the group taking only ICS were comparable for age, gender and clinical characteristics including FEV1. The analysis of therapeutic ranking steps showed that 55% of patients taking Pycnogenol® improved as judged by passing to a lower ICS dose step. In comparison, only 6% of patients depending exclusively on ICS progressed to a lower (ICS dose) therapeutic step. No deterioration (passage to a higher ICS therapeutic step) was observed in the Pycnogenol® group, whereas in 18.8% of patients depending exclusively on corticosteroids a deterioration requiring a higher dosage step was observed. The passage to different therapeutic steps was statistical significant between groups (P<0.05). Drop-outs were associated entirely to irregularities in follow-up and not due to medical reasons. No serious adverse events were observed in both groups and tolerability of Pycnogenol® was very good. The levels of asthma control in the 6 interventional months as compared to the same period in the previous year were compared. In the Pycnogenol® group, night-awakenings were less frequent, the number of days with PEF<80% were decreased, days with asthma score >1 were lower, requirement for salbutamol and additional asthma medication less frequent, and consultation of general practitioner and specialist required less commonly. All these parameters were statistical significantly improved in Pycnogenol® + ICS group versus the ICS control group where no considerable changes were observed. Various common signs and symptoms were evaluated by visual analog scale, (dry) cough, severity of chest symptoms, wheezing, dyspnea and daytime symptoms. In the ICS-only group values did not improve while they did improve significantly in the ICS + Pycnogenol® group (P<0.05 vs. ICS only group). A decrease by 15.2% of the specific IgE titer was found in the Pycnogenol® + ICS group, whereas the titer increased by 13.4% in the ICS-only group, while IgG1 and IgG4 remained unchanged in both groups. Pycnogenol® administration was effective for better control of signs and symptoms of allergic asthma and reduced the need for medication.


An ethnically relevant consensus Korean reference genome is a step towards personal reference genomes.
Human genomes are routinely compared against a universal reference. However, this strategy could miss population-specific and personal genomic variations, which may be detected more efficiently using an ethnically relevant or personal reference. Here we report a hybrid assembly of a Korean reference genome (KOREF) for constructing personal and ethnic references by combining sequencing and mapping methods. We also build its consensus variome reference, providing information on millions of variants from 40 additional ethnically homogeneous genomes from the Korean Personal Genome Project. We find that the ethnically relevant consensus reference can be beneficial for efficient variant detection. Systematic comparison of human assemblies shows the importance of assembly quality, suggesting the necessity of new technologies to comprehensively map ethnic and personal genomic structure variations. In the era of large-scale population genome projects, the leveraging of ethnicity-specific genome assemblies as well as the human reference genome will accelerate mapping all human genome diversity.


Ideas as art. Interview by Dane Cutu.
Three years ago, consultants Laurence Prusak and Thomas H. Davenport asked prominent management thinkers to name their gurus and reported the results in HBR. James G. March appeared on more lists than any other person except Peter Drucker. A professor emeritus in management, sociology, political science, and education at Stanford University, March has taught courses in subjects as diverse as organizational psychology, behavioral economics, leadership, rules for killing people, friendship, computer simulation, and statistics. He is perhaps best known for his pioneering contributions to organization and management theory. March's accomplishments in that field, and in many others, have conferred on him an almost unprecedented reputation as a rigorous scholar and a deep source of wisdom. As University of Chicago professor John Padgett wrote in the journal Contemporary Sociology, "March's influence, unlike that of any of his peers, is not limited to any possible subset of the social science disciplines; it is pervasive." March approaches thought aesthetically; he cares that ideas have "some form of elegance or grace or surprise." His poetic sensibility can be felt in the metaphors he has created over the years--the "garbage can theory" of organizational choice, for instance, and the "hot-stove effect" in learning. In this edited interview with HBR senior editor Diane Coutu, March shares his thinking on aesthetics, leadership, the role of folly, and the irrelevance of relevance when it comes to the pursuit of ideas. He also comments on the fundamental differences between academic and experiential knowledge, underscoring the need for both.


A Case Series of Imported Malaria Caused by Plasmodium falciparum in Kayseri and Review of Literature.
Malaria is a major worldwide public health problem. In the last years, no domestic cases of malaria have been detected and cases of imported malaria exist only in Turkey. In this study, clinical and laboratory findings of five Plasmodium falciparum (P. falciparum) malaria patients who were admitted to the emergency department between January 2013 and December 2015 were retrospectively presented. One of the patients was an African student, and the other patients had a history of travelling to Africa. Ring formation was observed when Giemsa staining was performed on the blood smears of all patients, and in three patients, P. falciparum was also detected using multiplex polymerase chain reaction (PCR) (Bio-Rad, United States of America). P. falciparum was not detected by PCR in the other two patients. Malaria should be primarily considered in febrile patients who have a history of travelling to endemic regions, and peripheral blood smears should definitely be examined.


PirB restricts ocular-dominance plasticity in visual cortex.
Experience can alter synaptic connectivity throughout life, but the degree of plasticity present at each age is regulated by mechanisms that remain largely unknown. Here, we demonstrate that Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, is expressed in subsets of neurons throughout the brain. Neuronal PirB protein is associated with synapses and forms complexes with the phosphatases Shp-1 and Shp-2. Soluble PirB fusion protein binds to cortical neurons in an MHCI-dependent manner. In mutant mice lacking functional PirB, cortical ocular-dominance plasticity is more robust at all ages. Thus, an MHCI receptor is expressed in central nervous system neurons and functions to limit the extent of experience-dependent plasticity in the visual cortex throughout life. PirB is also expressed in many other regions of the central nervous system, suggesting that it may function broadly to stabilize neural circuits.


Scaling data on inter-nation action.
We conclude (i) that the marker-card method is as reliable a measure as the ordinary Q-sort method; (ii) that Q and the marker-card score are measuring very nearly the same thing-in this case, presumably conflict; and (iii) that the use of marker cards permits comparison of judgments about a given quantity in the context of different situations and may even permit comparison of results obtained by different research teams if the different teams use the same marker decks. A fundamental issue involved in scoring the entries on the cards in this study by either Q-sort or marker cards is the "judgability" of the items as indicators of conflict. We noted above that items with the highest variances in scoring, from judge to judge, were concentrated at the low-conflict end of the scale. A possible explanation is that judges are able to make finer distinctions concerning an attribute when it is present than when it is absent. Differences in scoring could also arise from a lack of unidimensionality in the attribute being scaled. If juidges find that conflict has several distinct aspects, the task of placing items in a single order becomes more difficult. Difficulties in making judgments also arose from the fact that the actions were being judged out of context, or in contexts that varied from judge to judge, since no standard context was supplied. But these difficulties lie outside our problem, which was to find an alternative to Q-sorting which would permit intersituational comparisons. Our sLIccess in finding an alternative is apparent in our results, but problems of judgability remain with both techniques. Beyond providing a standard for intersitLiational comparisons, the markercard technique has other advantages. It is possible that the use of marker decks will be of help in training judges to score such a variable as conflict. In our study it permitted identification of a judge inadequately trained to do so. Possibly the marker cards will be useful in assigning scale values to hatches of data too small for Q-sort, or even to individual items. It further appears that the marker cards should be useful in discriminating among highconflict items which heretofore would all have tended to appear in the top Q-sort category. The marker-card technique has given us a reliable alternative to Q-sort for scaling conflict. The method should be capable of extension to dimensions other than conflict.


Unexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1.
Hepatitis C virus (HCV) infection remains a major health problem worldwide. HCV entry into host cells and membrane fusion are achieved by two envelope glycoproteins, E1 and E2. We report here the 3.5-Å resolution crystal structure of the N-terminal domain of the HCV E1 ectodomain, which reveals a complex network of covalently linked intertwined homodimers that do not harbour the expected truncated class II fusion protein fold.


Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex.
Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to βKlotho with high affinity and specifically activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on βKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.


Prevention of supraventricular arrhythmias after coronary artery bypass surgery. A meta-analysis of randomized control trials.
This meta-analysis was performed to determine the efficacy of digoxin, verapamil, and beta-adrenoceptor blockers as prophylaxis against supraventricular arrhythmias (SVAs) after coronary artery bypass graft surgery (CABG). Randomized control trials were included if the electrocardiographic monitoring technique was clearly defined and extended through at least the first 3 postoperative days. Twenty-four of 69 identified studies were included in the final analysis. A summary odds ratio (OR) of the likelihood of developing SVAs after CABG in the treatment versus control groups was calculated. The pooled mean ventricular rate during SVA in patients who developed such an arrhythmia was also calculated. Neither digoxin nor verapamil reduced the likelihood of SVAs after CABG (digoxin: OR = 0.97, 95% confidence interval [CI] = 0.62-1.49; verapamil: OR = 0.91, CI = 0.57-1.46). The likelihood of developing an SVA in patients treated with beta-blockers was markedly decreased compared with controls (OR = 0.28, CI = 0.21-0.36). The pooled ventricular rate when SVAs did occur was significantly lower in each of the treatment groups. Prophylactic beta-adrenoceptor blockers had a protective effect against the development of SVAs in a select population of patients undergoing CABG. No such beneficial effect was demonstrated for digoxin or verapamil. All three classes of agents reduced the ventricular rate in patients who developed the arrhythmia, although the ventricular rate reduction was not clinically optimal.


Effect of vasodilator and inotropic drugs on clinical symptoms and long-term survival in chronic congestive heart failure.
The major therapeutic goals in the treatment of congestive heart failure are the relief of symptoms and the prolongation of life, but it remains unclear whether there is a relation between changes in exercise tolerance and alterations in the risk of death. Although all vasodilator and inotropic agents produce short-term haemodynamic benefits, these acute effects do not predict the long-term clinical responses to these drugs. Converting-enzyme inhibitors appear to improve symptoms and survival. A combination of hydralazine and isosorbide dinitrate produces variable effects on exercise tolerance but appears to prolong life. Catecholamines and phosphodiesterase inhibitors may reduce dyspnea and fatigue but adversely affect mortality. Calcium channel blocking drugs may exert deleterious effects on both symptoms and prognosis. alpha-Adrenergic blocking drugs produce no beneficial or adverse effects on clinical status or mortality. Hence, there is no consistent relation between the symptomatic and prognostic effects of drug therapy in patients with chronic heart failure. This variability makes it impossible to predict the effects of any drug on exercise tolerance or survival based on an evaluation of the agent's short-term haemodynamic effects.


Abnormal cone structure in foveal schisis cavities in X-linked retinoschisis from mutations in exon 6 of the RS1 gene.
To evaluate macular cone structure in patients with X-linked retinoschisis (XLRS) caused by mutations in exon 6 of the RS1 gene. High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) in two patients with XLRS and 27 age-similar healthy subjects. Retinal structure was correlated with best-corrected visual acuity, kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The six coding exons and the flanking intronic regions of the RS1 gene were sequenced in each patient. Two unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic ERG b-wave was reduced more than the a-wave. SD-OCT showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. In each patient, a mutation in exon 6 of the RS1 gene was identified and was predicted to change the amino acid sequence in the discoidin domain of the retinoschisin protein. AOSLO images of two patients with molecularly characterized XLRS revealed increased cone spacing and abnormal packing in the macula of each patient, but cone coverage and function were near normal outside the central foveal schisis cavities. Although cone density is reduced, the preservation of wave-guiding cones at the fovea and eccentric macular regions has prognostic and therapeutic implications for XLRS patients with foveal schisis. (Clinical Trials.gov number, NCT00254605.).


Recommendations for the reporting of pleural mesothelioma.
It has been evident for decades that pathology reports are very variable even within a single institution. Standardization of reporting is the optimal way to ensure that information necessary for patient management, prognostic and predictive factor assessment, grading, staging, analysis of outcomes, and tumor registries is included in pathology reports. In recent years, 2 societies (first the Association of Directors of Anatomic and Surgical Pathology [ADASP] and then the College of American Pathologists [CAP]) have undertaken to publish guidelines for the reporting of common cancers. The CAP assigned multidisciplinary groups of pathologists, surgeons, radiation, and medical oncologists to develop the protocols. Other pathologists and clinicians then reviewed them. After those reviews the protocols were reviewed by multiple CAP committees and finally approved by the Board of Governors. The ADASP, in contrast, chose a pathologist expert in each filed to assemble a group from within the pathology community (with clinician input if desired) to write specific cancer protocols. These were then approved by the ADASP council and subsequently by the membership. Although both societies began the process at approximately the same time, the streamlined approach adopted by the ADASP enabled them to publish years earlier in pathology journals frequented by anatomic pathologists. Although the formats are somewhat different, the contents are essentially the same. The American College of Surgery Commission on Cancer (COC) accredits cancer centers in the United States. Recently, the COC decided to require elements, deemed as essential by the CAP, to be described in all pathology reports in their accredited cancer centers as of January 2004. Importantly, they do not require that the specific CAP protocols or synoptic reports be used. The ADASP has updated all of its protocols to comply with the COC requirements in the form of 37 uniform checklists. The checklists use the staging criteria sited in the American Joint Committee on Cancer 2002 Staging Manual (sixth edition) but include a variety of other references listed in each of the checklists. Moreover, the checklists are formatted for ease of use. They may be used as templates for uniform reporting and are designed to be compatible with voice-activated transcription. The different elements in these revised ADASP diagnostic checklists have been divided into required and optional. The term required in this context only signifies compliance with the COC guidelines. The ADASP realizes that specimens and practices vary, and it will not be possible to report these elements in every case. However, the ADASP hopes that pathologists will find these checklists to be useful in daily clinical practice, while facilitating compliance with the new COC requirements.


Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.
Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted.


Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-α in the retina.
The detrimental role of TNF-α in ischemia-induced tissue damage is known. The authors study examined whether opioid receptor activation alters TNF-α levels in the postischemic retina. Retinal ischemia was induced by raising the intraocular pressure above systolic blood pressure (155-160 mm Hg) for 45 minutes. Rats were pretreated with the opioid receptor agonist morphine (1 mg/kg; intraperitoneally) before injury. Selected animals were pretreated with the opioid antagonist naloxone (3 mg/kg; intraperitoneally). Human optic nerve head (ONH) astrocytes and rat microglial cells were treated with morphine (0.1-1 μM) for 24 hours and then treated with 10 μg/mL or 30 ng/mL lipopolysaccharide (LPS), respectively. TNF-α was measured by ELISA. Opioid receptor subtypes in astrocytes and microglia were determined by Western blot analysis. There was a time-dependent increase in TNF-α production; the maximum production occurred at 4 hours after ischemia and localized to the inner retinal regions. Ischemia-induced TNF-α production was significantly inhibited by morphine. In astrocytes and microglia, LPS triggered a robust increase in the release of TNF-α, which was significantly inhibited (P < 0.05) by morphine. Naloxone reversed the morphine-induced suppression of TNF-α production in vivo and in vitro. Both ONH astrocytes and microglial cells expressed δ-, κ-, and μ-opioid receptor subtypes. These data provide evidence that the production of TNF-α after ischemia/reperfusion injury is an early event and that opioid receptor activation reduces the production of TNF-α. Immunohistochemistry data and in vitro studies provide evidence that ONH astrocytes and microglial cells are the primary sources for the TNF-α production under ischemic/inflammatory conditions. Activation of one or more opioid receptors can reduce ischemic/reperfusion injury by the suppression of TNF-α production.


Birthweight and the risk for type 2 diabetes mellitus in adult women.
Previous reports have suggested an association between birthweight and type 2 diabetes mellitus. To investigate the association between birthweight and type 2 diabetes in a large cohort of adult women, taking into account potential explanatory factors in childhood and adult life. Cohort study. Birthweight was ascertained at the end of follow-up. The Nurses' Health Study, a cohort of 121,701 U.S. women born from 1921 to 1946 who have been followed since 1976. 69,526 women in the Nurses' Health Study who were free of diabetes at baseline and reported their own birthweight on the 1992 questionnaire. 2123 cases of confirmed type 2 diabetes diagnosed from 1976 to 1992. Low birthweight was associated with increased risk for type 2 diabetes. Age-adjusted relative risks suggested a reverse J-shape association between birthweight and risk for type 2 diabetes. However, after adjustment for adult body mass index and maternal history of diabetes, an inverse association across the entire range of birthweight became apparent; compared with the reference group, relative risks by ascending birthweight category were 1.83 (95% CI, 1.55 to 2.16) for birthweight less than 5.0 lb, 1.76 (CI, 1.49 to 2.07) for birthweight 5.0 to 5.5 lb, 1.23 (CI, 1.11 to 1.37) for birthweight 5.6 to 7.0 lb, 0.95 (CI, 0.82 to 1.10) for birthweight 8.6 to 10.0 lb, and 0.83 (CI, 0.63 to 1.07) for birthweight of more than 10 lb (P for trend < 0.001). Adjustment for ethnicity, childhood socioeconomic status, and adult lifestyle factors did not substantially alter this association. The association between birthweight and risk for type 2 diabetes was strongest among women whose mothers had no history of diabetes. Birthweight is inversely associated with risk for type 2 diabetes during adulthood. Examination of prenatal nutrition and other potential in utero determinants of both birthweight and risk for type 2 diabetes may yield new means to prevent type 2 diabetes.


Cholinergic neurons mediate intestinal propulsion in the rat.
Cholinergic influences on intestinal propulsion were determined in vivo in fasted rats by measuring the movement of a nonabsorbable radioactive marker along the intestine following treatment with cholinergic drugs. The marker was instilled directly into the intestine via a previously implanted cannula. The direct effects of cholinergic drugs on intestinal contractions were determined in vitro using isolated segments of duodenum and jejunum. Neostigmine (0.1 mg/kg) produced a marked increase in intestinal transit that was blocked by atropine pretreatment (1.0 mg/kg) but not hexamethonium pretreatment (20 mg/kg). Atropine pretreatment alone significantly delayed transit while hexamethonium treatment alone did not affect intestinal transit. Neostigmine produced a concentration-dependent (0.3-30 microM) increase in contractions in both duodenal and jejunal segments in vitro. Prior incubation of the tissues with atropine (10(-7) M) blocked the neostigmine-induced contractions while prior incubation with hexamethonium (10(-6) M) did not. Contractions produced by substance P were not affected by atropine or hexamethonium. These data indicate that enhancement of cholinergic neurotransmission by neostigmine treatment increased intestinal propulsion and that this effect was mediated at muscarinic cholinergic receptors. Furthermore, inhibition of ongoing cholinergic transmission by atropine treatment reduced intestinal propulsion. The increase in transit produced by neostigmine may result from a stimulation of intestinal contractions. Cholinergic neurons are important mediators of intestinal propulsion in the rat as in other species.


Detection of human papillomavirus DNA by DNA chip in breast carcinomas of Korean women.
It remains unclear whether there is an association between human papillomavirus (HPV) infection and human breast cancer. The aim of this study was to investigate the presence of HPV DNA in breast carcinomas of Korean women and to examine the possible association between HPV and breast cancer development. For this purpose, HPV DNAs from 154 patients, including 123 patients with breast carcinoma and 31 with intraductal papilloma, and nipple tissue from 27 cancer patients were examined using the DNA chip method. HPV DNA was detected in 8 breast carcinomas (6.5%) but in no intraductal papilloma. All detected HPV genotypes were of high-risk groups. There was a slightly increased incidence in papillary carcinomas (11.5%) and invasive ductal carcinomas with adjacent intraductal papillomas (11.8%) compared to the other histological subtypes (3.2-4.3%), although the difference was not statistically significant (p = 0.126). The presence of HPV DNA was not correlated with specific prognostic predictors of disease. High-risk HPV DNA sequences were present in 6.5% of Korean patients with breast tumors. However, this study could not demonstrate whether or not such HPVs directly contribute to the development of breast cancer.


Assessment of respiratory symptoms and asthma prevalence in a U.S.-Mexico border region.
The authors studied children who were 10-12 yr of age and who resided in sister cities in a U.S.-Mexico border region to determine the prevalence of asthma and respiratory symptoms. The relationship of symptoms to ambient levels of particulate matter less than 10 microm in diameter (PM10), and to several indoor environmental conditions, was assessed. The study was conducted in the border cities of Ambos Nogales (Nogales, Arizona [United States], and Nogales, Sonora [Mexico]). At the beginning of the 11-wk study, during the autumn of 1996, 631 students and their parents completed baseline questionnaires. While in school, the children completed daily symptom diaries and daily peak expiratory flow maneuvers. PM10 values and daily temperatures were also measured. The authors found that the prevalence of self-reported asthma among 5th-grade students was comparable on both sides of the border (i.e., 7.6% on the Arizona side and 6.9% on the Sonora side). Wheezing was a frequent complaint (29.5-35.6%), as was cough (16.8-29.6%). Smoking in the home was common on both sides of the border, and it was associated with a greater occurrence of self-reported asthma and respiratory complaints. Increased respiratory symptoms were also associated with increased ambient PM10 levels. The prevalence of respiratory symptoms such as wheezing and frequent cough among all children in this study, combined with the limitations inherent in self-reporting, suggest that asthma may actually be more prevalent than has been previously reported.


Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver.
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.


An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency.
Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown-Vialetto-Van Laere and Fazio-Londe syndromes since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients present with a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal. Considerable progress in the clinical and genetic diagnosis of RTDs has been made in recent years and has permitted the successful lifesaving treatment of many patients with high dose riboflavin supplementation. In this review, we first outline the importance of riboflavin and its efficient transmembrane transport in human physiology. Reports on 109 patients with a genetically confirmed diagnosis of RTD are then summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. Finally, we focus attention on recent work with different models of RTD that have revealed possible pathomechanisms contributing to neurodegeneration in patients.


Influence of antigen structure on the activation and induction of unresponsiveness in cloned human T lymphocytes.
Using cloned human helper T lymphocytes reactive with a 24 amino acid peptide (p20) of the carboxyl terminal of the HA-1 molecule of influenza haemagglutinin we have investigated the influence of antigen structure on the activation and in the induction of antigen specific unresponsiveness of T cells. For this analysis stereoisomers and structural isomers of p20 have been constructed. P20 in the form of a single loop created by a disulphide based between residue 306 and an additional cysteine at position 330 was able to activate the helper T cells in the presence of accessory cells but unable to induce tolerance. This result suggested that critical residues were prevented from direct interaction with the T-cell receptor and/or the MHC Class II determinants and required processing to expose them. The enantiomer (D-p20) and the inverted sequence (retro-L-p20) which have non complementary side chain topography as compared to the parent peptide neither activated nor tolerized the T cells. Furthermore the retro-D-p20 isomer which has the same side chain topography as L-p20 but with a reversal of amino and carboxyl acid groups also failed to stimulate or tolerize. Therefore T-cell antigen recognition is not determined by side chains alone. The results presented suggest that structure of extrinsic antigen influences T-cell antigen recognition.


Presumed mast cell choroidal infiltrate in aggressive systemic mastocytosis.
To report a rare case of a unilateral choroidal mast cell infiltration in a patient with aggressive systemic mastocytosis (ASM). The patient is a man in his fifties with a diagnosis of ASM. He developed visual complaints in the right eye associated with an area of subretinal fluid on fundus examination. Visual acuity at presentation was 20/150 in the right eye and 20/25 in the left eye. After ophthalmic and radiologic imaging workup, the patient was diagnosed with presumed choroidal mast cell infiltrate. The index of suspicion was high due to the prior ASM diagnosis. External beam radiation and intravitreal injection treatments were offered but the patient declined. The patient was switched from interferon to a new targeted systemic therapy for ASM, midostaurin. Despite some mixed, temporary response in systemic symptoms/signs of ASM at four months, the choroidal lesion and subretinal fluid were stable with visual acuity at 20/125. Mast cell choroidal infiltration in ASM should be considered as part of the differential with acute/subacute vision changes. Diagnosis requires exclusion of other possibilities with ocular imaging and in this case, monitoring for development of other malignancies in which there were none. Midostaurin's ocular response was not on par with systemic response. Additional localized ocular therapies may be required.


ATP-Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles.
ATP sensitive potassium channels (KATP ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. KATP channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the KATP current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.


Spatiotemporal changes in diffusion, T2 and susceptibility of white matter following mild traumatic brain injury.
Impaired white matter integrity in traumatic brain injury (TBI) can lead to deficits in various neurological functions. The differentiation of the underlying pathological processes, e.g. edema, demyelination, axonal damage, to name a few, is of key clinical interest for the assessment of white matter injury. In this study, a combination of T2 , diffusion and susceptibility MRI was used to study the spatiotemporal changes in white matter at 1 h, 3 h, and 1, 2, 7 and 14 days following TBI, using a rat controlled cortical impact (CCI) model. Based on radial diffusivity (RD), the rats were divided into two groups: group 1 showed widespread increases in RD along the corpus callosum of the ipsilesional hemisphere at day 2, and group 2 showed normal RD. Based on this group separation, group 1 also showed similar widespread changes in fractional anisotropy (FA) and T2 at day 2, and group 2 showed normal FA and T2 . The widespread changes in RD and T2 in group 1 on day 2 were apparently dominated by edema, which obscured possible myelin and axonal damage. In contrast, the susceptibility of group 1 showed more localized increases near the impact site on day 2, and otherwise similar contrast to the contralesional hemisphere. The localized susceptibility increase is probably a result of demyelination and axonal injury. The extent of brain damage between the two groups revealed by MRI was consistent with behavioral results, with the first group showing significantly increased forelimb asymmetry and increased forelimb foot fault deficits. Our results suggest that the combination of T2 , diffusion and susceptibility MRI may provide an opportunity for the differential assessment of edema and axonal damage in TBI. Copyright © 2016 John Wiley & Sons, Ltd.


Sputum induction for microbiological diagnosis of childhood pulmonary tuberculosis in a community setting.
Sputum induction has increasingly enabled microbiological confirmation of pulmonary tuberculosis (PTB) in hospitalised children, but it has not been evaluated in a community setting. To investigate the yield, feasibility and safety of sputum induction for the diagnosis of TB in children in a primary health care facility. A prospective study in a primary health care clinic in South Africa from April 2007 to June 2009. Consecutive children with clinically suspected PTB, with a household adult PTB contact or human immunodeficiency virus infected with respiratory symptoms were enrolled. History, clinical examination, tuberculin skin test and chest X-ray results were recorded. Two sequential induced sputum specimens were obtained for smear and culture. A total of 270 children were enrolled (median age 38 months); sputum induction was successful in 269 (99%); 65 (24%) children were clinically diagnosed, of whom 11 (16.9%) were microbiologically confirmed. An additional 18 children not clinically diagnosed had microbiological confirmation of PTB and were placed on TB treatment thereafter, increasing the diagnostic yield by 21.6%, from 65 to 83 cases. Sputum induction procedures were well tolerated; no major adverse events occurred. Sputum induction is feasible and safe in a community setting. Sputum induction was useful for making a microbiological diagnosis, increasing the number of children diagnosed and treated for PTB.


Gelam honey attenuated radiation-induced cell death in human diploid fibroblasts by promoting cell cycle progression and inhibiting apoptosis.
The interaction between ionizing radiation and substances in cells will induce the production of free radicals. These free radicals inflict damage to important biomolecules such as chromosomes, proteins and lipids which consequently trigger the expression of genes which are involved in protecting the cells or repair the oxidative damages. Honey has been known for its antioxidant properties and was used in medical and cosmetic products. Currently, research on honey is ongoing and diversifying. The aim of this study was to elucidate the role of Gelam honey as a radioprotector in human diploid fibroblast (HDFs) which were exposed to gamma-rays by determining the expression of genes and proteins involved in cell cycle regulation and cell death. Six groups of HDFs were studied viz. untreated control, irradiated HDFs, Gelam honey-treated HDFs and HDF treated with Gelam honey pre-, during- and post-irradiation. HDFs were treated with 6 mg/ml of sterilized Gelam honey (w/v) for 24 h and exposed to 1 Gray (Gy) of gamma-rays at the dose rate of 0.25 Gy/min. Our findings showed that, gamma-irradiation at 1 Gy up-regulated ATM, p53, p16ink4a and cyclin D1 genes and subsequently initiated cell cycle arrest at G0/G1 phase and induced apoptosis (p < 0.05). Pre-treatment with Gelam honey however caused down regulation of these genes in irradiated HDFs while no significant changes was observed on the expression of GADD45 and PAK genes. The expression of ATM and p16 proteins was increased in irradiated HDFs but the p53 gene was translated into p73 protein which was also increased in irradiated HDFs. Gelam honey treatment however significantly decreased the expression of ATM, p73, and p16 proteins (p < 0.05) while the expression of cyclin D1 remained unchanged. Analysis on cell cycle profile showed that cells progressed to S phase with less percentage of cells in G0/G1 phase with Gelam honey treatment while apoptosis was inhibited. Gelam honey acts a radioprotector against gamma-irradiation by attenuating radiation-induced cell death.


Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.
Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.


GAPPadder: a sensitive approach for closing gaps on draft genomes with short sequence reads.
Closing gaps in draft genomes is an important post processing step in genome assembly. It leads to more complete genomes, which benefits downstream genome analysis such as annotation and genotyping. Several tools have been developed for gap closing. However, these tools don't fully utilize the information contained in the sequence data. For example, while it is known that many gaps are caused by genomic repeats, existing tools often ignore many sequence reads that originate from a repeat-related gap. We compare GAPPadder with GapCloser, GapFiller and Sealer on one bacterial genome, human chromosome 14 and the human whole genome with paired-end and mate-paired reads with both short and long insert sizes. Empirical results show that GAPPadder can close more gaps than these existing tools. Besides closing gaps on draft genomes assembled only from short sequence reads, GAPPadder can also be used to close gaps for draft genomes assembled with long reads. We show GAPPadder can close gaps on the bed bug genome and the Asian sea bass genome that are assembled partially and fully with long reads respectively. We also show GAPPadder is efficient in both time and memory usage. In this paper, we propose a new approach called GAPPadder for gap closing. The main advantage of GAPPadder is that it uses more information in sequence data for gap closing. In particular, GAPPadder finds and uses reads that originate from repeat-related gaps. We show that these repeat-associated reads are useful for gap closing, even though they are ignored by all existing tools. Other main features of GAPPadder include utilizing the information in sequence reads with different insert sizes and performing two-stage local assembly of gap sequences. The results show that our method can close more gaps than several existing tools. The software tool, GAPPadder, is available for download at https://github.com/Reedwarbler/GAPPadder .