Occupational Safety and Work-Related Injury Control Efforts in Qatar: Lessons Learned from a Rapidly Developing Economy.
Work-related injury (WRI) control is an integral part of occupational safety. In rapidly developing Gulf countries such as Qatar with a predominantly expatriate workforce, WRI control is a complex issue often seen in conjunction with the implementation of labour laws and labour rights. We aimed to implement a public health approach to facilitate efforts to achieve long-term WRI control in Qatar. A range of initiatives helped to gain visibility and momentum for this important public health problem, including identifying and engaging with key stakeholders, workers' surveys, steps to establish a unified injury database, and the implementation of a WRI identification tool in the electronic medical records. A contemporaneous improved enforcement of existent occupational safety regulations through heightened worksite inspections and efforts to improve living conditions for migrant workers also took place. WRIs are not only a Qatar-specific problem; the same issues are faced by neighbouring Gulf countries and other rapidly developing economies with large expatriate worker populations. These strategies are also useful starting points for similar countries interested in nurturing a safe, healthy and productive workforce.


Exoelectrogenic capacity of host microbiota predicts lymphocyte recruitment to the gut.
Electrotaxis, directional cell movement in response to an electric potential, has been demonstrated in a wide range of cell types including lymphocytes. Exoelectrogens, microorganisms capable of generating electrical currents, have been identified in microbial fuel cells. However, no studies have investigated exoelectrogenic microbes in fresh feces or the effects of an exoelectrogenic microbiota on the host organism. Here we show that commensal gut microbial populations differ in their capacity for electrical current production by exoelectrogens and that those differences are predictive of increased lymphocyte trafficking to the gut in vivo, despite the lack of increased production of canonical lymphocyte-specific chemokines. Additionally, we demonstrate that the difference in current production between mice purchased from different commercial sources correlates reproducibly with the presence or absence of segmented filamentous bacteria, and while our data do not support a direct role for segmented filamentous bacteria in ex vivo current production, an exoelectrogenic microbiota can be transferred in vivo via mucosa-associated bacteria present in the ileum. Moreover, we detect upregulation of microbial genes associated with extracellular electron transfer in feces of mice colonized with exoelectrogenic microbiota containing segmented filamentous bacteria. While still correlative, these results suggest a novel means by which the gut microbiota modulates the recruitment of cells of the immune system to the gut.


Possible cases of leprosy from the Late Copper Age (3780-3650 cal BC) in Hungary.
At the Abony-Turjányos dűlő site, located in Central Hungary, a rescue excavation was carried out. More than 400 features were excavated and dated to the Protoboleráz horizon, at the beginning of the Late Copper Age in the Carpathian Basin, between 3780-3650 cal BC. Besides the domestic and economic units, there were two special areas, with nine-nine pits that differed from the other archaeological features of the site. In the northern pit group seven pits contained human remains belonging to 48 individuals. Some of them were buried carefully, while others were thrown into the pits. The aim of this study is to present the results of the paleopathological and molecular analysis of human remains from this Late Copper Age site. The ratio of neonates to adults was high, 33.3%. Examination of the skeletons revealed a large number of pathological cases, enabling reconstruction of the health profile of the buried individuals. Based on the appearance and frequency of healed ante- and peri mortem trauma, inter-personal (intra-group) violence was characteristic in the Abony Late Copper Age population. However other traces of paleopathology were observed on the bones that appear not to have been caused by warfare or inter-group violence. The remains of one individual demonstrated a rare set of bone lesions that indicate the possible presence of leprosy (Hansen's disease). The most characteristic lesions occurred on the bones of the face, including erosion of the nasal aperture, atrophy of the anterior nasal spine, inflammation of the nasal bone and porosity on both the maxilla and the bones of the lower legs. In a further four cases, leprosy infection is suspected but other infections cannot be excluded. The morphologically diagnosed possible leprosy case significantly modifies our knowledge about the timescale and geographic spread of this specific infectious disease. However, it is not possible to determine the potential connections between the cases of possible leprosy and the special burial circumstances.


Analysis of theta power in hippocampal EEG during bar pressing and running behavior in rats during distinct behavioral contexts.
These experiments examine changes in theta power as measured by wavelet analysis in five rats performing a conditional visual discrimination task and a simple running task. In the conditional task, rats were trained to press one lever to initiate a trial and then to press one of two choice levers, each corresponding to one of two cue lights. Analysis of theta power in this operant task found a large decrease in theta power during the choice bar presses, in contrast to the increase in theta power during trial initiation bar presses. This result seems to stand counter to results that propose consistent relationships between motor actions and theta power (Vanderwolf, EEG Clin Neurophys 26:407-418, 1969), as well as studies suggesting that the lack of bar-press theta is the result of habituation. However, these data can be seen as being in broad agreement with the theoretical framework of sensorimotor integration (Bland and Oddie, Behav Brain Res 127:119-136, 2001). To investigate further the power of theta observed at the termination of type 1 motor activity, a runway task was devised in which rats ran back and forth between two ends of a linear track, one of which was always rewarded and the other never rewarded. Theta power decreased sharply 240 ms before movement ended at the rewarded end, but not at the unrewarded end of the track. These data extend the current scope of theory in demonstrating that hippocampal theta activity can end abruptly 200-400 ms prior to the end of type 1 motor movement when approaching the end of a motor sequence.


Abdominal MR: liver and pancreas.
Following the introduction of rapid, high-quality scan techniques and the development of new, tissue-specific contrast agents, the applications of MRI for abdominal imaging are experiencing unprecedented growth. This article examines the current status of liver and pancreatic MRI, highlighting technical and methodological approach, use of contrast agents, and main clinical applications. The MRI technique appears to be the ideal diagnostic tool for detection and characterization of benign and malignant liver neoplasms, and for evaluating tumor response after nonsurgical treatments. Dynamic imaging after bolus injection of a gadolinium chelate is currently a fundamental component of an MRI examination of the liver in many instances. Optimal dynamic scanning depends on the use of a multisection spoiled gradient-echo technique that allows one to image the entire region of interest during a single suspended respiration. Images are obtained during four phases relative to the injection of the contrast agent: precontrast, arterial (pre-sinusoidal), portal (sinusoidal), and delayed (extracellular) phase. Liver-specific contrast agents, including hepatobiliary agents and reticuloendothelial system-targeted iron oxide particles, however, may offer advantages over gadolinium chelates in some clinical settings. Computed tomography is still preferred to MRI for imaging the pancreas. However, state-of-the-art MRI may currently be at least as accurate as spiral CT for depiction of inflammatory and neoplastic pancreatic diseases. Moreover, MRI has the advantage of allowing simultaneous investigation of the biliary tree, owing to cholangiopancreatography techniques. Hence, a comprehensive assessment of most pancreatic diseases can be achieved with a single examination.


Biomechanical response of the bovine pia-arachnoid complex to tensile loading at varying strain-rates.
The pia-arachnoid complex (PAC) covering the brain plays an important role in the mechanical response of the brain due to impact or inertial loading. However, the mechanical properties of the pia-arachnoid complex and its influence on the overall response of the brain have not been well characterized. Consequently, finite element (FE) brain models have tended to oversimplify the response of the pia-arachnoid complex, possibly resulting in a loss of accuracy in the model predictions. The aim of this study was to determine, experimentally, the material properties of the pia-arachnoid complex under quasi-static and dynamic loading conditions. Specimens of the pia-arachnoid complex were obtained from the parietal and temporal regions of freshly slaughtered bovine subjects with the specimen orientation recorded. Single-stroke, uniaxial quasi-static and dynamic tensile experiments were performed at strain-rates of 0.05, 0.5, 5 and 100 s(-1) (n = 10 for each strain rate group). Directional differences of the pia-arachnoid complex were also investigated. Results from this study revealed the pia-arachnoid complex was rate-dependent and isotropic, suggesting that the pia-arachnoid complex can provide omnidirectional support and load bearing to the adjacent brain tissue during an impact.


Incidence of cardioembolic stroke including paradoxical brain embolism in patients with acute ischemic stroke before and after the Great East Japan Earthquake.
The incidence of heart disease or deep vein thrombosis (DVT) reportedly increased after the Great East Japan Earthquake. We hypothesized that the incidence of cardioembolic stroke (CES) including paradoxical brain embolism (PBE) among patients with acute stroke would increase after the earthquake due to cessation of antithrombotic therapy or the increase in heart disease and DVT associated with the evacuation. The aim of this study is to evaluate the changes in the prevalence of DVT and the incidence of CES including PBE in acute ischemic stroke before and after the earthquake. We retrospectively studied 1,044 consecutive ischemic stroke patients (73.1 ± 12.5 years old, male 61.5%) who were admitted to a comprehensive stroke center (from January 2010 through March 2012) located in the earthquake disaster area within 7 days after stroke onset. The prevalence of DVT and the incidence of CES including PBE were compared before and after the earthquake of 11 March 2011. The median of the initial National Institutes of Health Stroke Scale (NIHSS) scores was 4 (interquartile range: 1-8). Two hundred and eighty-two patients (27.0% of those surveyed) were diagnosed with CES. After adjustment for sex, age, NIHSS score, and patient's residential address, the proportion of CES patients was significantly increased after the earthquake (odds ratio, OR 1.61, 95% confidence interval, 95% CI: 1.20-2.17). Eighty-nine patients (8.5% of those surveyed) had DVT. Compared with 2010 findings, the prevalence of DVT was significantly increased in the fourth quarter of 2011 and the first quarter of 2012 (OR 1.85, 95% CI: 1.05-3.24). Nineteen (1.8% of those surveyed) were diagnosed with PBE. The proportion of PBE patients was also significantly increased in the second half of 2011 (OR 3.69, 95% CI: 1.28-12.1). The incidence of CES was significantly increased after the earthquake, compared with the period before the earthquake. We encountered more PBE in the period from 3 to 9 months after the earthquake and found more DVT in the acute ischemic stroke patients in the period from 6 through 12 months after the earthquake. In these types of disasters, we have to ensure the distribution of drugs, including antithrombotics, and support the prevention of DVT in the refugees.


Cognitive Symptom Awareness Among Patients With Multiple Sclerosis Using a Mobile Application.
Cognitive impairment is a common complication in persons with multiple sclerosis (MS). Using a mobile application has been shown to improve patient's awareness of cognitive symptoms. The purpose of this quality improvement project was to improve awareness of cognitive symptoms in adult patients with MS using a mobile application. A pre/post-implementation quality improvement design was used. Patients were instructed to download the application MS Care Connect. Patients completed a pre/post-questionnaire regarding their awareness of cognitive symptoms and if they were likely to discuss symptoms with providers. They were instructed to use the application to rate the severity of their cognitive symptoms at least weekly. Thirty-two patients completed both pre- and post-implementation questionnaires. No significant change in awareness of cognitive symptoms was found; however, patients were more likely to discuss cognitive changes with their healthcare team. In the 18 patients who used the application, a total of 60 cognitive symptom ratings were reported. Nurses may recommend use of a mobile application for patients to track their cognitive symptoms; however, further research is needed. This project showed that adding a mobile application did not change awareness of patients' cognitive symptoms.


Missense mutations in a transmembrane domain of the Komagataeibacter xylinus BcsA lead to changes in cellulose synthesis.
Cellulose is synthesized by an array of bacterial species. Komagataeibacter xylinus is the best characterized as it produces copious amounts of the polymer extracellularly. Despite many advances in the past decade, the mechanisms underlying cellulose biosynthesis are not completely understood. Elucidation of these mechanisms is essential for efficient cellulose production in industrial applications. In an effort to gain a better understanding of cellulose biosynthesis and its regulation, cellulose crystallization was investigated in K. xylinus mutants resistant to an inhibitor of cellulose I formation, pellicin. Through the use of forward genetics and site-directed mutagenesis, A449T and A449V mutations in the K. xylinus BcsA protein were found to be important for conferring high levels of pellicin resistance. Phenotypic analysis of the bcsAA449T and bcsAA449V cultures revealed that the mutations affect cellulose synthesis rates and that cellulose crystallinity is affected in wet pellicles but not dry ones. A449 is located in a predicted transmembrane domain of the BcsA protein suggesting that the structure of the transmembrane domain influences cellulose crystallization either by affecting the translocation of the nascent glucan chain or by allosterically altering protein-protein interactions.


Monoamine oxidases: the biochemistry of the proteins as targets in medicinal chemistry and drug discovery.
Monoamine oxidase (MAO, EC.184.108.40.206) has been a drug target for 60 years, with the primary rationale of developing drugs to treat neuropsychiatric disorders. The biological importance of MAO is to regulate amine levels is the brain and to metabolize amines and drugs in the periphery. This review of the biochemistry of MAO A and MAO B describes the functional properties of the two enzymes integrated with knowledge of the structures of the many MAOinhibitor complexes published in the last 10 years. The analysis of activity, and the chemical and kinetic mechanisms are discussed. Inhibition studies on human MAO in vitro are now facilitated by assays using readily available materials but the kinetics of MAO involving alternative oxidative pathways and sensitivity to the oxygen concentration mean that careful analysis of the data is required as well as the good practice of determining mechanism of inhibition and kinetic constants. Kinetic constants can then be compared with thermodynamic calculations. Inhibitors bind to both the oxidized and reduced forms of MAO present during turnover so both forms should be considered when using molecular dynamics to facilitate drug design. Interaction of inhibitors with the active site can be detected as changes in the visible spectrum and these changes can provide clues about the flavin adduct formed for irreversible inhibitors or about the proximity to the flavin for reversible inhibitors. Developing areas (knock-out mice for behavior, the imidazoline binding site, and imaging to monitor the activity and the inhibition of MAO in the patient) are mentioned.


Distribution of muscarinic acetylcholine receptors and presynaptic nerve terminals in amphibian heart.
At many synapses, neurotransmitter receptor molecules in the postsynaptic membrane are selectively concentrated at a site directly opposite the presynaptic nerve terminal. In this paper, I examine acetylcholine (ACh) receptor distribution in cardiac muscle in relatin to the distribution of presynaptic axonal varicosities. The density of varicosities, stained with zinc iodide and osmium, ranges from 0.7/100 micrometer 2 in ventricle to 1.9/100 micrometer 2 in sinus venosus. It is estimated that < 3% of the muscle surface is apposed to presynaptic varicosities. ACh receptors, however, are randomly distributed on the muscle surface and not concentrated in patche. ACh receptor distribution was determined by iontophoretic application of ACh and mapping of ACh sensitivity and by [3H]QNB (quinuclidinyl benzilate) binding and autoradiography [3H]QNB binds with > 90% specificity to a single, saturable, high-affinity (Kd = 11.1 pM at 21 degrees C) class of binding sites. QNB binding sites are thought to correspond to ACh receptors, because muscarinic agonists compete for [3H]QNB binding and produce a hyperpolarization in the sinus venosus with the same order of potency. The concentrations of QNB binding sites in the sinus and atria are about twice those found in ventricle. The receptor density corresponds to the density of innervation measured by zinc iodide and osmium staining. Autoradiographic experiments show that [3H]QNB binding sites are distributed randomly over the entire surface of the muscle. This distribution of ACh receptors in cardiac muscle has important implications for the function of the cardiac neuroeffector junction.


Growth of Allescheria boydii in anitbiotic-containing media.
Cazin, John, Jr. (University of Iowa, Iowa City), and David W. Decker. Growth of Allescheria boydii in antibiotic-containing media. J. Bacteriol. 90:1308-1313. 1965.-Thirteen isolates of Allescheria boydii were surveyed for their ability to grow and sporulate on media containing cycloheximide and chloramphenicol. The fungus grew well in the presence of 4 to 8 mg/ml of cycloheximide, whereas ascocarps and coremia were always inhibited at a concentration of the drug lower than that required to inhibit growth and conidial production. In certain strains, ascocarp production was inhibited by concentrations of cycloheximide (0.4 mg/ml) normally used in selective media; however, two strains produced mature ascocarps at a concentration of 1 mg/ml of the antibiotic, and two strains produced immature ascocarps at a concentration of 4 mg/ml. Growth inhibition was not observed with concentrations of chloramphenicol as high as 1,000 mg per liter in any of eight strains tested.


The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort.
The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery. We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups. We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups. We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials.


HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes.
The transcription factor HIF-1alpha plays a crucial role in modifying gene expression during low oxygen tension. In a previous study, we demonstrated that HIF-1alpha is essential for chondrocyte growth arrest and survival in vivo. To explore further the role of HIF-1alpha in cartilage biology, we undertook studies with primary epiphyseal chondrocytes with a targeted deletion of HIF-1alpha. In this study, we show that HIF-1alpha is necessary for regulating glycolysis under aerobic and anaerobic conditions. HIF-1alpha-null chondrocytes were unable to maintain ATP levels in hypoxic microenvironments, indicating a fundamental requirement for this factor for the regulation of chondrocyte metabolism. Synthesis of the angiogenic factor vascular endothelial growth factor was also significantly induced by hypoxia, and this increase is lost in HIF-1alpha-null mutant cells. Under hypoxic conditions, aggrecan mRNA and protein levels were significantly reduced in chondrocytes lacking the HIF-1alpha transcription factor. Interestingly, strongly increased type-II collagen protein levels were detected in wild-type cells after 44 hours of hypoxia. In addition, type-II collagen mRNA and protein levels were strongly decreased under low oxygen in chondrocytes lacking HIF-1alpha. In summary, our results clearly demonstrate the importance of HIF-1alpha in maintenance of anaerobic glycolysis, and thereby extracellular matrix synthesis, of epiphyseal chondrocytes.


Eastern chimpanzees, but not bonobos, represent a simian immunodeficiency virus reservoir.
Chimpanzees in west central Africa (Pan troglodytes troglodytes) are endemically infected with simian immunodeficiency viruses (SIVcpzPtt) that have crossed the species barrier to humans and gorillas on at least five occasions, generating pandemic and nonpandemic forms of human immunodeficiency virus type 1 (HIV-1) as well as gorilla SIV (SIVgor). Chimpanzees in east Africa (Pan troglodytes schweinfurthii) are also infected with SIVcpz; however, their viruses (SIVcpzPts) have never been found in humans. To examine whether this is due to a paucity of natural infections, we used noninvasive methods to screen wild-living eastern chimpanzees in the Democratic Republic of the Congo (DRC), Uganda, and Rwanda. We also screened bonobos (Pan paniscus) in the DRC, a species not previously tested for SIV in the wild. Fecal samples (n = 3,108) were collected at 50 field sites, tested for species and subspecies origin, and screened for SIVcpz antibodies and nucleic acids. Of 2,565 samples from eastern chimpanzees, 323 were antibody positive and 92 contained viral RNA. The antibody-positive samples represented 76 individuals from 19 field sites, all sampled north of the Congo River in an area spanning 250,000 km(2). In this region, SIVcpzPts was common and widespread, with seven field sites exhibiting infection rates of 30% or greater. The overall prevalence of SIVcpzPts infection was 13.4% (95% confidence interval, 10.7% to 16.5%). In contrast, none of the 543 bonobo samples from six sites was antibody positive. All newly identified SIVcpzPts strains clustered in strict accordance to their subspecies origin; however, they exhibited considerable genetic diversity, especially in protein domains known to be under strong host selection pressure. Thus, the absence of SIVcpzPts zoonoses cannot be explained by an insufficient primate reservoir. Instead, greater adaptive hurdles may have prevented the successful colonization of humans by P. t. schweinfurthii viruses.


Suppression or enhancement by superoxide dismutase of tumor cell killing by macrophages of normal donors and breast cancer patients.
This study was designed to examine the role superoxide production by macrophages plays in tumor killing. When superoxide dismutase was added to the normal macrophage-tumor cell (MA-160 cell line) suspensions macrophage mediated tumor cytotoxicity was suppressed. In contrast, superoxide dismutase often greatly enhances the cytotoxic ability of macrophages from breast cancer patients. To determine whether the inability of breast cancer patients' macrophages to kill tumor cells might be related to decreased levels of O2- production, we measured the amount of O2- generated by both normal and breast cancer patients' macrophages. The macrophages obtained from the normal donors produced 46.0 +/- 6.7 nanomoles O2-/10(6) macrophages per 10 minutes (mean +/- S.E. of 9 donors). In contrast, macrophages from the four breast cancer patients who possessed cytotoxic macrophages produced 56.4 +/- 5.2 nanomoles O2-/10(6) macrophages per 10 minutes whereas those from the 6 breast cancer patients who possessed non-cytotoxic macrophages produced 18.6 +/- 3.2 nanomoles O2-/10(6) macrophages per 10 minutes. Thus, it appears that there is a relationship between macrophage cytotoxicity and the level of O2- produced. Furthermore, it is possible that the inability to generate sufficient amounts of O2- might explain the inability of breast cancer patients' macrophages to kill tumor cells in some cases.


Diffusion-weighted magnetic resonance is better than polymerase chain reaction for early diagnosis of herpes simplex encephalitis: a case report.
Herpes simplex virus infection of the central nervous system is still a significant cause of morbidity and often mortality. Early diagnosis is critical because treatment with the antiviral drug acyclovir dramatically decreases morbidity and mortality in children. The use of polymerase chain reaction techniques is a diagnostic procedure in herpes simplex virus infection, but negative polymerase chain reaction test results of cerebrospinal fluid herpes simplex virus can occur within the first 72 hours of illness, with subsequent test results becoming positive as in this case. Therefore, diffusion-weighted magnetic resonance may play a major role as a first and early diagnostic step.


A comparative multi-site and whole-body assessment of fascia in the horse and dog: a detailed histological investigation.
Fascia in the veterinary sciences is drawing attention, such that physiotherapists and animal practitioners are now applying techniques based on the concept of fascia studies in humans. A comprehensive study of fascia is therefore needed in animals to understand the arrangement of the fascial layers in an unguligrade horse and a digitigrade dog. This study has examined the difference between the horse and the dog fascia at specific regions, in terms of histology, and has compared it with the human model. Histological examinations show that in general the fascia tissue of the horse exhibits a tight and dense composition, while in the dog it is looser and has non-dense structure. Indeed, equine fascia appears to be different from both canine fascia and the human fascia model, whilst canine fascia is very comparable to the human model. Although regional variations were observed, the superficial fascia (fascia superficialis) in the horse was found to be trilaminar in the trunk, yet multilayered in the dog. Moreover, crimping of collagen fibers was more visible in the horse than the dog. Blood vessels and nerves were present in the loose areolar tissue of the superficial and the profound compartment of hypodermis. The deep fascia (fascia profunda) in the horse was thick and tightly attached to the underlying muscle, while in the dog the deep fascia was thin and loosely attached to underlying structures. Superficial and deep fascia fused in the extremities. In conclusion, gross dissection and histology have revealed species variations that are related to the absence or presence of the superficial adipose tissue, the retinacula cutis superficialis, the localization and amount of elastic fibers, as well as the ability to slide and glide between the different layers. Further research is now needed to understand in more detail whether these differences have an influence on the biomechanics, movements and proprioception of these animals.


The calcium channel antagonist, nimodipine, decreases operant self-administration of low concentrations of ethanol.
This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol.


Textural Changes by Mastication and Proper Food Texture for Patients with Oropharyngeal Dysphagia.
Bolus texture is a key factor for safe swallowing in patients with dysphagia since an improper texture may result in aspiration and/or pharyngeal residue. This article discusses swallowing bolus texture from two key aspects: the textural change of solid food by mastication and the current standardized definition of food texture in Japan. When swallowing a liquid bolus, the texture is mostly maintained from ingestion to swallow onset. For solid food, however, the food is crushed by chewing and mixed with saliva before swallowing; the texture of the ingested food is modified to an easily swallowable form at swallow onset by mastication. Understanding the mechanism of mastication and its assessment are therefore important in deciding the proper diet for dysphagic patients. As standardized criteria for classifying the texture of food and liquid are essential as well, this report also describes the Japanese Dysphagia Diet 2013 that is commonly used as the standardized index for dysphagic diets in Japan.


Assessment of the influence of different sample processing and cold storage duration on plant free proline content analyses.
A method which is widely accepted for the analysis of free proline content in plant tissues is based on the use of 3% sulfosalicylic acid as an extractant, followed by spectrophotometric quantification of a proline-ninhydrin complex in toluene. However, sample preparation and storage may influence the proline actually measured. This may give misleading or difficult to compare data. To evaluate free proline levels fresh and frozen strawberry (Fragaria × ananassa Duch.) leaves and soybean [Glycine max (L.) Merr.] hypocotyl tissues were used. These were ground with or without liquid nitrogen and proline extracted with sulfosalicylic acid. A particular focus was the influence of plant sample cold storage duration (1, 4 and 12 weeks at -20°C) on tissue proline levels measured. The free proline content analyses, carried out in leaves of Fragaria × ananassa Duch. as well as in hypocotyls of Glycine max (L.) Merr., showed a significant influence of the sample preparation method and cold storage period. Long-term storage of up to 12 weeks at -20°C led to a significant increase in the measured proline in all samples analysed. The observed changes in proline content in plant tissue samples stored at -20°C indicate the likelihood of the over-estimation of the proline content if the proline analyses are delayed. Plant sample processing and cold storage duration seem to have an important influence on results of proline analyses. Therefore it is recommended that samples should be ground fresh and analysed immediately.


Comparative studies of herpesvirus papio (baboon herpesvirus) DNA and Epstein-Barr virus DNA.
An Epstein-Barr virus (EBV)-like herpesvirus has been isolated from a baboon cell line (594S/F9) by induction with the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The herpesvirus papio (HVP) DNA was mixed with B95 EBV DNA and was characterized by sedimentation in neutral glycerol gradient as 55S DNA, with a buoyant density of approx. 1.718 g/ml after equilibrium centrifugation in caesium chloride. DNA-DNA reassociation kinetics between B95 EBV and HVP DNA showed that HVP DNA shares about 40% homology with B95 EBV DNA. Blot hybridization of EcoRI fragments of HVP DNA with a 32P-B95 EBV DNA probe showed that most of the EcoRI fragments of HVP DNA were hybridized to B95 EBV DNA, suggesting that the homologous sequences were dispersed throughout the virus DNA.


[Multicenter study of the effects of sulbactam/cefoperazone on bacterial infections in the fields of internal medicine focused mainly on respiratory infections in Tochigi Prefecture].
Clinical effects of sulbactam/cefoperazone (SBT/CPZ) was studied on variety of bacterial infections in the fields of internal medicine focused mainly on respiratory infections. The total 135 infections were consisted of 103 respiratory infections, 15 urinary tract infections, 4 sepsis, 7 biliary tract infections, and 6 other infections, of which 86 patients had underlying diseases. The daily doses of SBT/CPZ were 2 to 6 g divided into 2 to 3 times i.v. or d.i.v., and the duration of administration was from 3 to 35 days. The clinical effects were judged by the attending doctors based on the changes in fever, cough, rales, chest rentogenograms, white blood cell counts, CRP values, ESR, etc. The total efficacy rate was 76.9%, and 69.0% of the isolated organism was eradicated by SBT/CPZ. The side effect was noted in 1 case, and the abnormal laboratory findings were noted in 1 case, however it was difficult to determine whether they were due to SBT/CPZ. These results suggest that the clinical usefulness of SBT/CPZ for the infections in the fields of internal medicine.


Development of a Transferable Reactive Force Field of P/H Systems: Application to the Chemical and Mechanical Properties of Phosphorene.
We developed ReaxFF parameters for phosphorus and hydrogen to give a good description of the chemical and mechanical properties of pristine and defected black phosphorene. ReaxFF for P/H is transferable to a wide range of phosphorus- and hydrogen-containing systems including bulk black phosphorus, blue phosphorene, edge-hydrogenated phosphorene, phosphorus clusters, and phosphorus hydride molecules. The potential parameters were obtained by conducting global optimization with respect to a set of reference data generated by extensive ab initio calculations. We extended ReaxFF by adding a 60° correction term, which significantly improved the description of phosphorus clusters. Emphasis was placed on the mechanical response of black phosphorene with different types of defects. Compared to the nonreactive SW potential ( Jiang , J.-W. Nanotechnology 2015 , 26 , 315706 ), ReaxFF for P/H systems provides a significant improvement in describing the mechanical properties of the pristine and defected black phosphorene, as well as the thermal stability of phosphorene nanotubes. A counterintuitive phenomenon is observed that single vacancies weaken the black phosphorene more than double vacancies with higher formation energy. Our results also showed that the mechanical response of black phosphorene is more sensitive to defects in the zigzag direction than that in the armchair direction. In addition, we developed a preliminary set of ReaxFF parameters for P/H/O/C to demonstrate that the ReaxFF parameters developed in this work could be generalized to oxidized phosphorene and P-containing 2D van der Waals heterostructures. That is, the proposed ReaxFF parameters for P/H systems establish a solid foundation for modeling of a wide range of P-containing materials.


Antimalarial evaluation of the chemical constituents of hairy root culture of Bixa orellana L.
Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug-resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.


Influence of heat stress on arterial baroreflex control of heart rate in the baboon.
The influence of environmental heat stress on the arterial baroreflex control of heart rate (HR) was studied in eight conscious, chronically instrumented baboons. Inflations of balloon occluders around the inferior vena cava (IVC) and thoracic descending aorta (DA) were used to produce acute, graded changes in mean arterial blood pressure (MABP) in 5 mm Hg intervals ranging from +/- 5 to +/- 25 mm Hg. After determination of the HR responses to changes in MABP in the normothermic baboon (blood temperature less than or equal to 37.6 degrees C), the animal was subjected to environmental heating to produce hyperthermia. When blood temperature reached approximately 39.5 degrees C, HR responses to graded DA and IVC occlusions were again determined. During hyperthermia, the HR sensitivity (delta HR/ delta MABP) to MABP changes was markedly diminished for reductions in MABP and significantly enhanced for increases in MABP. To determine whether these alterations in the HR response to changes in MABP were due to an alteration of the baroreflex control of HR, full, sigmoid-shaped HR-MABP curves for both the normothermic and hyperthermic states were constructed and characterized by total HR range, estimated slope of the steep portion of the curve, and MABP at the midpoint of the HR range (BP50). During hyperthermia (1) the whole HR-MABP curve shifted significantly upward by 35-40 beats/min, (2) total HR range, the estimated slope, and BP50 did not change, and (3) the control point (pre-occlusion HR-MABP value) curves were also constructed during either beta-adrenergic blockade or cholinergic (Ch)-receptor blockade in the normothermic and hyperthermic state. Similar to that seen for the unblocked heart, the whole HR-MABP curves were also shifted upward during hyperthermia in this group of baboons with no alteration in the total HR range, the estimated slope, or BP50. The upward shift in the HR-MABP curve during Ch-receptor blockade, unlike during beta-receptor blockade, was much greater than that which could be attributed only to the local effect of blood temperature. Although the control point was also shifted upward along the steep portion of the curve during beta- or Ch-receptor blockade, the upward shift observed during beta-adrenergic blockade was similar to that observed in the unblocked state. Thus, a heat stress-induced hyperthermia produces a rise in HR without significantly altering the characteristics of the reflex control of HR by arterial baroreceptors. To rely solely on changes in HR sensitivity may lead to erroneous conclusions as to the effect of a particular stress on the baroreceptor reflex control of HR. Further, these results indicate that: (1) the upward shift in the HR-MABP curve is mediated by both the local effect of blood temperature on HR and cardiac sympathetic efferent neurons which are independent of the baroreceptor reflex, and (2) the upward shift in the control point is mediated predominantly by vagal withdrawal, probably as part of the compensatory response to a heat-induced hypotension.


Validity of a Food and Fluid Exercise Questionnaire for Macronutrient Intake during Exercise against Observations.
Information about the accuracy of self-reported food and fluid intake during competitions is scarce. The objective of this study was to validate a previously developed food and fluid exercise questionnaire (FFEQ) against direct observations made during competitions in athletes. Fifty-eight recreational endurance athletes participating in four different running events and one cross duathlon in the Netherlands between 2015 and 2017 were recruited. The FFEQ overestimated the median energy and carbohydrate intake by 27.6 kcal/h (20.6%) and 9.25 g/h (30.8%) (p < 0.001), respectively, compared to direct observation. Reporting bias (i.e., correlation between the difference between methods and average of both methods) increased with a higher energy (r: 0.41, p < 0.01) and carbohydrate intake (r: 0.44, p < 0.01). No statistically significant difference was found between FFEQ-reported fluid intake per hour and observations (median difference: -2.93 mL, -1.1%; p = 0.48) and no fluid reporting bias was identified (r: 0.23, p = 0.08). FFEQ-reported energy (r: 0.74), carbohydrate (r: 0.74), and fluid (r: 0.85) intake was strongly correlated with the observed intake (all p-values < 0.001). In conclusion, the FFEQ accurately estimates the fluid intake on a group level during competitions in recreational athletes. Even though FFEQ overestimates the energy and carbohydrate intake, it is still a useful tool for ranking individuals based on their intake.


B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage.
B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.


Recent advances in the development of selective small molecule inhibitors for cyclin-dependent kinases.
Loss of normal cell cycle regulation is the hallmark of human cancers, and alteration of the components involved in cell cycle regulation occurs in most human tumors. This suggests that Cyclin dependent kinases (CDKs) are an attractive target for the development of pharmacological agents for the treatment of cancer. Recently, CDK family members that are not directly involved in cell cycle regulation have been identified. This includes CDK7, CDK8, and CDK9, which participate in transcription regulation, and CDK5, which plays a role in neuronal and secretory functions. Given the involvement of CDKs in multiple cellular processes, development of selective small molecule inhibitors for specific CDKs is expected to help clarify whether improved specificity of cell cycle CDK inhibitors will enhance their therapeutic potential in cancer treatment. Selective inhibitors are also needed as tools to explore the biology of diseases in which CDKs may participate and to help develop therapeutics to treat them. Intensive screening and drug design based on CDK/inhibitor co-crystal structure and SAR studies have led to the identification of a large variety of chemical inhibitors of CDKs. Although they are competitive with ATP at the catalytic site, their kinase selectivity varies greatly, and inhibitors selective for certain CDKs have begun to be identified. There are currently two categories of selective CDK inhibitors: those that are selective for CDK2 and CDK1 and those that are selective for CDK4/6. These two types of inhibitors have different effects on tumor cells and are expected to be useful in the treatment of cancer.


Web-based resources for retrieving health policy information: NLM and beyond.
This paper identifies Web-based resources of interest to the health policy community. Both information useful for developing health policy and information about existing health policy are included. Resources described are classified into three major categories: traditional and grey literature, statistical and epidemiological data, and legal and legislative material. National Library of Medicine (NLM) resources include MEDLINE, DIRLINE, HealthSTAR, HSRProj, and HSTAT. In addition, NLM's National Information Center on Health Services Research and Health Care Technology (NICHSR) has a Web page (http:/(/)www.nlm.nih.gov/nichsr/nichsr.++ +html) that provides an extensive listing of health-policy-related Web sites. Some of the other resources highlighted include those available from the Health Care Financing Administration (HCFA), the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC), the National Committee for Vital and Health Statistics (NCVHS), and the Library of Congress.


Tissue partition and risk assessments of trace elements in Indo-Pacific Finless Porpoises (Neophocaena phocaenoides) from the Pearl River Estuary coast, China.
Throughout the last few decades, an increased number of stranded marine mammals, particularly the Indo-Pacific Finless Porpoises (Neophocaena phocaenoides), were observed in the Pearl River Estuary (PRE). As long-lived, apex predators vulnerable to bioaccumulation of contaminants, the tissue residue levels and health risk of trace elements (TEs) in N. phocaenoides from the PRE have been little studied. Eleven typical TEs distributed in skin, liver and kidney tissues were investigated from 25 specimens stranded along the PRE from 2007 to 2015 in the present study. It revealed that most TEs were highly accumulated in internal organs (liver and kidney), except for Zn with high residue levels in external skin. Compared with the TEs in prey items, the residue levels of Hg, Se, Zn, Cu, Cd and Cr in N. phocaenoides increased 4-618 times, indicating a potentially significant biomagnification. Sex-related differences of TE accumulation were not obvious, except for renal Mn, in which the females showed lower mean concentrations than males. Significantly positive correlations between body length and TE levels were found for Hg, Se and Cd. Results of the calculated risk quotients (RQ) suggested that the risks to N. phocaenoides from consumption of prey items were generally low, but further attentions should be paid to Cd, Cr, Cu, Hg and As due to the elevated RQ values. The concentrations of Hg, Cd and Se in the epidermis were positively correlated with the levels found in internal organs. Our investigation provides evidence to support the use of skin as one biomonitoring approach on Hg, Cd and Se contamination of internal tissues in this species.


Risk Factors for Smoking in Rural Women: The Role of Gender-Based Sexual and Intimate Partner Violence.
Women living in Ohio Appalachia experience cervical cancer at disproportionately high rates. Intimate partner and sexual gender-based violence (GBV) and smoking are independent risk factors for cervical cancer and interact to heighten risk. Appalachian women smoke at higher rates than other Ohio women, but little is known about GBV exposure in the region. The purpose of this study was to establish prevalence of women's exposure to GBV in Ohio Appalachia and examine the association between GBV and smoking among women in the region. A two-phase address-based random sampling approach was used in three purposefully selected Ohio Appalachian counties to identify women to complete an interviewer administered cross-sectional survey (n = 398). The primary exposure variable was GBV Index Score, a 4 level indices representing increasing exposure to eight abuse types. Correlation analysis and logistic regression were used to examine smoking correlations and risk. Almost 57% of women in the three selected Ohio Appalachian counties experienced GBV, with rate increasing to 77.5% among current smokers. The distribution of the GBV Exposure Index Score was significantly different across smoking status (p < = 0.0001), with exposure of GBV increasing when moving from never, to former, to current smokers. When controlling for depression, age, and adult socioeconomic position, GBV Exposure Index was significantly associated with current smoking behavior (OR:1.62, 95% CI [1.21-2.17]). Professionals working to reduce disparate disease burden among women in Ohio Appalachia should consider the role GBV plays in health behavior and behavioral change interventions, including smoking and smoking cessation.


Clinical results between single incision laparoscopic cholecystectomy and conventional 3-port laparoscopic cholecystectomy: prospective case-matched analysis in single institution.
The aim of our study was to compare single incision laparoscopic cholecystectomy (SILC) and conventional laparoscopic cholecystectomy (CLC) with respect to clinical outcomes. Patients with less than a 28 body mass index (BMI) and a benign gall bladder disease were enrolled in this study. From January 2011 to February 2012, 30 consecutive patients who underwent SILC were compared with 30 patients who underwent CLC during the same period. In this study, all operations were performed by one surgeon. In each group, patient characteristics and perioperative data were collected. There was no significant difference in the preoperative characteristics. There was no significant difference in the postoperative laboratory result (alanine aminotransferase, aspartate aminotransferase, and alanine aminotransferase), number of conversion and complication cases, and length of hospital stay. The operation time was significantly longer in the SILC group (78.5 ± 17.8 minutes in SILC group vs. 34.9 ± 5.75 minutes in CLC group, P < 0.0001). The total nonsteroidal antiinflammatory drug usage during perioperative period showed significantly higher in SILC groups (162 ± 51 mg in the SILC group vs. 138 ± 30 mg in the CLC group), but there was no statistically significant difference in opioid usage between two groups. The postoperative pain score was significantly higher in the SILC group at second, third, and tenth postoperative day. Satisfaction of postoperative wound showed superiority in SILC group. SILC seems to be an acceptable alternative to CLC with acceptable results. However, it is not enough to propose any real benefits of SILC when compared with CLC in terms of operation time and postoperative pain.


Immunohistochemical demonstration of simple epithelia-type keratin intermediate filament in a case of Merkel cell carcinoma.
A case of Merkel cell carcinoma that developed on the right cheek of a 77-year-old woman is reported. The diagnosis was ultrastructurally made by demonstrating dense-core granules in the cytoplasm of the tumor cells. Immunohistochemically, the tumor cells were shown to possess simple epithelia-type keratin intermediate filaments, but no neurofilaments. This finding was in accordance with that obtained on normal Merkel cells. No bioactive peptides examined could be detected in the tumor cells. Typing of intermediate filaments in tumor cells may be one of the important markers, along with the ultrastructural findings, in diagnosing Merkel cell carcinoma.


Condoned or condemned: the situational affordance of anger and shame in the United States and Japan.
Two studies tested the idea that the situations that people encounter frequently and the situations that they associate most strongly with an emotion differ across cultures in ways that can be understood from what a culture condones or condemns. In a questionnaire study, N = 163 students from the United States and Japan perceived situations as more frequent to the extent that they elicited condoned emotions (anger in the United States, shame in Japan), and they perceived situations as less frequent to the extent that they elicited condemned emotions (shame in the United States, anger in Japan). In a second study, N = 160 students from the United States and Japan free-sorted the same situations. For each emotion, the situations could be organized along two cross-culturally common dimensions. Those situations that touched upon central cultural concerns were perceived to elicit stronger emotions. The largest cultural differences were found for shame; smaller, yet meaningful, differences were found for anger.


Correlational study and randomised controlled trial for understanding and changing red meat consumption: The role of eating identities.
The present studies aimed to contribute to the literature on psychological variables involved in reducing red meat consumption (RMC). Study 1 investigated whether the theory of planned behaviour (TPB), plus healthy-eating and meat-eating identities, could explain intentions to reduce RMC. Study 2 evaluated the effectiveness of an SMS text message intervention on self-monitoring to reduce RMC. In Study 1, data were collected daily using online food diaries for one week and a TPB questionnaire. Study 2 was a randomised controlled trial assessing pre- and post-RMC and TPB constructs by online food diaries and questionnaires over a one-week period. Participants were Italian undergraduates in each study (Study 1: N = 405; Study 2: N = 244). In Study 2, participants were randomly allocated to control and message condition groups. Participants in the message condition group received a daily SMS, which reminded them to monitor RMC, while participants in the control group did not receive any message. Only students who completed all measures were considered in the analyses (Study 1: N = 342; Study 2: N = 228). Study 1 showed that affective and instrumental attitudes, perceived behavioural control, and meat-eating identity explained intentions to reduce RMC, while subjective norm, past behaviour, and healthy-eating identity did not. Study 2 showed that an SMS intervention was effective in increasing intentions and reducing RMC. Mediation analyses indicated partial serial mediation through healthy-eating and meat-eating identities and intentions. The present studies provide support for the predictive validity of TPB in explaining intentions to reduce RMC and for the efficacy of an SMS intervention targeting self-monitoring in reducing RMC. Findings confirmed the important role of eating identities in explaining intentions to reduce RMC and in changing this behaviour.


Sexual rights but not the right to health? Lesbian and bisexual women in South Africa's National Strategic Plans on HIV and STIs.
Synergies between securing sexual rights and the right to health have been pursued where there are clear public health gains to be made, such as lowering incidence of HIV and other sexually transmitted infections (STI). South Africa's 1996 Constitution outlawed discrimination on the basis of sexual orientation and promoted the right to health. This qualitative health policy analysis sought to understand why and how interventions to improve sexual health of lesbian and bisexual women and address sexual violence were initially proposed in the HIV & AIDS and STI Strategic Plan for South Africa 2007-2011 and why and how these concerns were deprioritised in the National Strategic Plan (NSP) on HIV, STIs and TB 2012-2016. A conceptual framework considered several determinants of political priority for the inclusion in NSP development in 2007 and 2011 around sexual health concerns of women who have sex with women. This article presents findings from 25 in-depth key informant interviews and document review and highlights results of application of categories for a framework on determinants of political priority for lesbian and bisexual women's issues to be included in South Africa's NSP including: actor power, ideas, political context and issue characteristics. The article demonstrates how the epidemiological and structural drivers of lesbian and bisexual women's vulnerability to HIV and STIs, including sexual violence and other violations of their sexual rights, have been expressed in policy forums and whether this has made an impact on lesbian and bisexual women's ability to claim the right to health.


Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis.
Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06-1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = -0.05 [-0.06 to -0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35-2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12-1.70). Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.


Effect of cortisol on the thiol content of rat liver nuclear proteins.
Administration of cortisol to normal or adrenalectomized rats leads within 15-30min to an increased thiol content of nuclear proteins, measured by the incorporation of iodo[(3)H]-acetate or N-[(14)C]ethylmaleimide or by colorimetric methods. The same effect is observed after incubation of isolated rat liver nuclei with corticosteroids. The increased thiol content of the nuclear proteins shows the same time-dependence as the stimulation of RNA synthesis by corticosteroids observed in vivo and in vitro. Amino acid analysis of the carboxymethylated proteins reveals that in the experiments in vivo most of the label is present as carboxymethylcysteine with small amounts of carboxymethyl-lysine and carboxymethylhistidine, whereas in the experiments in vitro more carboxymethyl-lysine and carboxymethylhistidine than carboxymethylcysteine are found. The increase in the content of thiol groups is due to cleavage of the disulphide bridges between the nuclear proteins. Polyacrylamide-gel electrophoresis of the acid-soluble fraction reveals that most of the iodo[(3)H]acetate label is incorporated into a non-histone fraction with a molecular weight of approx. 45000 whereas in the acid-insoluble fractions many protein bands are labelled.


Empowering parents for evidence-based fever management: An integrative review.
Many parents of young, febrile children lack evidence-based tools to manage fever (knowledge, skills, confidence, support), fear negative outcomes, and prioritize the reduction of fever over management of its source. This review examines the literature for evidence of factors that must be considered when designing effective fever management educational interventions for parents, especially those whose health literacy is low. A systematic search identified studies from 1980 to 2011 using the databases PubMed, CINAHL, Embase, Cochrane Review, Web of Science, PsychInfo, Medline Plus, Joanna Briggs Institute, and Google Scholar. The most effective educational interventions are 1:1, multidimensional, structured, relevant, and reinforced over time. Parental culture, health literacy, knowledge deficits, and beliefs must be addressed by nurse practitioners (NPs) to maximize evidence-based behaviors. Parents often strive to do what is best for their child but may become overly protective and anxious when managing their child's fever. NPs have a prime opportunity to improve parents' fever management practices. An evidence-based toolkit, created with respect for those who may have low health literacy, will give parents tangible tools to help them provide safer and less costly care for their febrile child.


[Chronic hepatitis C/autoimmune hepatitis overlap syndrome: report of two cases].
The coexistence of non-organ specific autoantibodies and chronic hepatitis C features raises the dilemma as to whether the pathogenesis is viral or autoimmune and consequently to be treated with interferon or corticosteroids. Two cases with autoimmune characteristics and chronic hepatitis C are reported. We discuss the possibility of classifying this overlap form in three distinct entities: viral disease with an autoimmune epiphenomenon ("false hepatitis C/autoimmune hepatitis overlap syndrome"), viral disease associated to an autoimmune pathogenic component ("true hepatitis C/autoimmune hepatitis overlap syndrome") and false serological anti-HCV positivity in classical autoimmune hepatitis. In our experience the interferon/corticosteroid association was successful.


Generation and Characterization of Iduronidase-Cleavable ADCs.
A crucial design feature for the therapeutic success of antibody-drug conjugates (ADCs) is the linker that connects the antibody with the drug. Linkers must be stable in circulation and efficiently release the drug inside the target cell, thereby having a fundamental impact on ADC pharmacokinetics and efficacy. The variety of enzymatically cleavable linkers applied in ADCs is limited, and some are believed to be associated with unwanted side effects due to the expression of cleavage-mediating enzymes in nonmalignant cells. Based on a bioinformatic screen of lysosomal enzymes, we identified α-l-iduronidase (IduA) as an interesting candidate for ADC linker cleavage because of its low expression in normal tissues and its overexpression in several tumor types. In the present study, we report a novel IduA-cleavable ADC linker using exatecan and duocarmycin as payloads. We showed the functionality of our linker system in cleavage assays using recombinant IduA or cell lysates and compared it to established ADC linkers. Subsequently, we coupled iduronide-exatecan via interchain cysteines or iduronide-duocarmycin via microbial transglutaminase (mTG) to an anti-CEACAM5 (aCEA5) antibody. The generated iduronide-exatecan ADC showed high serum stability and similar target-dependent tumor cell killing in the subnanomolar range but reduced toxicity on nonmalignant cells compared to an analogous cathepsin B-activatable valine-citrulline-exatecan ADC. Finally, in vivo antitumor activity could be demonstrated for an IduA-cleavable duocarmycin ADC. The presented results emphasize the potential of iduronide linkers for ADC development and represent a tool for further balancing out tumor selectivity and safety.


Neuropathology for the neuroradiologist: rosettes and pseudorosettes.
The neuropathologic diagnosis of brain tumors entails the microscopic examination of conventional formalin-fixed paraffin-embedded tissue samples surgically removed from a radiographically defined lesion. A preliminary diagnosis is often rendered with frozen sections, though the final or definitive diagnosis usually requires more elaborate studies. Typically, the tissue is first fixed for a minimum of several hours in 10% neutral buffered formalin, processed through a series of dehydrating and clearing reagents, and embedded in a hardening wax, such as paraffin. The latter enables the tissue to be thinly sliced with a microtome, transferred to a glass slide, and then stained with dyes such as hematoxylin-eosin (H&E) that contrast the different cellular elements. Pathologists rely on visual clues such as pattern recognition when examining the stained tissue with a microscope, much as radiologists rely on gray-scale patterns of densities and intensities on images. Some histologic patterns of cellular architecture are distinctive if not pathognomonic, whereas others are less specific, but nevertheless considerably narrow the differential diagnosis. The precise biologic bases for some of the observed microscopic patterns are poorly understood, though their recognition remains useful nonetheless. Although more advanced methods of tissue examination--such as histochemical and immunohistochemical profiling, genetic analysis, and electron microscopy--have been developed, the microscopic review of H&E-stained material remains a critical component of tumor diagnosis.


Atomistic Molecular Dynamics Simulations of Charged Latex Particle Surfaces in Aqueous Solution.
Charged particles in aqueous suspension form an electrical double layer at their surfaces, which plays a key role in suspension properties. For example, binder particles in latex paint remain suspended in the can because of repulsive forces between overlapping double layers. Existing models of the double layer assume sharp interfaces bearing fixed uniform charge, and so cannot describe aqueous binder particle surfaces, which are soft and diffuse, and bear mobile charge from ionic surfactants as well as grafted multivalent oligomers. To treat this industrially important system, we use atomistic molecular dynamics simulations to investigate a structurally realistic model of commercial binder particle surfaces, informed by extensive characterization of particle synthesis and surface properties. We determine the interfacial profiles of polymer, water, bound and free ions, from which the charge density and electrostatic potential can be calculated. We extend the traditional definitions of the inner and outer Helmholtz planes to our diffuse interfaces. Beyond the Stern layer, the simulated electrostatic potential is well described by the Poisson-Boltzmann equation. The potential at the outer Helmholtz plane compares well to the experimental zeta potential. We compare particle surfaces bearing two types of charge groups, ionic surfactant and multivalent oligomers, with and without added salt. Although the bare charge density of a surface bearing multivalent oligomers is much higher than that of a surfactant-bearing surface at realistic coverage, greater counterion condensation leads to similar zeta potentials for the two systems.


Developing a Core Set of Outcome Measures for Behçet Disease: Report from OMERACT 2016.
The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group has been working toward developing a data-driven core set of outcome measures for use in clinical trials of Behçet's syndrome [Behçet disease (BD)]. This paper summarizes the group's work through OMERACT 2016, discussions during the meeting, and the future research agenda. Qualitative patient interviews were conducted among 20 patients with BD who have different types of organ involvement. A 3-round Delphi among BD experts and patients was initiated to identify domains, subdomains, and outcomes to be assessed in clinical trials of BD. The results of these studies were discussed during OMERACT 2016 and next steps were planned. Patients' perspectives and priorities were identified through qualitative interviews that identified candidate domains and subdomains for inclusion in the Delphi and characterized some shortcomings of the currently used patient-reported outcomes in BD. The first round of the Delphi was completed and several domains or subdomains were endorsed by the experts and/or the patients. Because many more items were endorsed than would be feasible to assess during a clinical trial, rating and ranking of items by physicians and patients was planned as a next critical step. The challenges of assessing specific organ system involvement was also discussed. The OMERACT Behçet Syndrome Working Group research program will identify core domains for assessment in BD with the goal of developing a core set of outcome measures for use in all trials of BD with the option to incorporate additional outcomes for specific organ involvement.


A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain.
Rationale: Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG). Methods: Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model. Results: BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection. In vivo adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF in vitro and reduce CFA-induced mechanical allodynia and heat hyperalgesia in vivo. The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats. Conclusions: Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.


[The clinico-echocardiographic characteristics of commissural mitral stenosis].
Overall 200 patients with rheumatic valvular heart disease were examined. Commissural mitral stenosis (CMS) was revealed in 70 patients (35%). At the preliminary examination stage CMS was not detected in 57% of patients, the tone of mitral valve opening could not be heard in 40%, normal configuration of the heart was preserved in 20% of patients according to the roentgenography data. The echocardiographic features of CMS were revealed: the lack of a cupola-shaped diastolic curvature of the mitral cusp in part of patients, an insignificant narrowing of the left venous opening.


The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp110.
Grp170 and Hsp110 proteins constitute two evolutionary distinct branches of the Hsp70 family that share the ability to function as nucleotide exchange factors (NEFs) for canonical Hsp70s. Although the NEF mechanism of the cytoplasmic Hsp110s is well understood, little is known regarding the mechanism used by Grp170s in the endoplasmic reticulum. In this study, we compare the yeast Grp170 Lhs1 with the yeast Hsp110 Sse1. We find that residues important for Sse1 NEF activity are conserved in Lhs1 and that mutations in these residues in Lhs1 compromise NEF activity. As previously reported for Sse1, Lhs1 requires ATP to trigger nucleotide exchange in its cognate Hsp70 partner Kar2. Using site-specific cross-linking, we show that the nucleotide-binding domain (NBD) of Lhs1 interacts with the NBD of Kar2 face to face, and that Lhs1 contacts the side of the Kar2 NBD via its protruding C-terminal alpha-helical domain. To directly address the mechanism of nucleotide exchange, we have compared the hydrogen-exchange characteristics of a yeast Hsp70 NBD (Ssa1) in complex with either Sse1 or Lhs1. We find that Lhs1 and Sse1 induce very similar changes in the conformational dynamics in the Hsp70. Thus, our findings demonstrate that despite some differences between Hsp110 and Grp170 proteins, they use a similar mechanism to trigger nucleotide exchange.


Prevalence and consequences of subacute ruminal acidosis in German dairy herds.
The prevalence and the clinical consequences of subacute ruminal acidosis (SARA) in dairy cows are still poorly understood. In order to evaluate the prevalence of SARA, 26 German dairy farms were included in a field study. In each herd, between 11 and 14 lactating dairy cows were examined for their ruminal pH using rumenocentesis. Milk production data and farm management characteristics were recorded. Each farm was scored for lameness prevalence among lactating animals, and body condition score was recorded three times four to five weeks apart in all animals examined. Farms were grouped on basis of ruminal pH and compared for lameness, body condition, milk production parameters and style of management. Animals were grouped on basis of their measured ruminal pH and compared accordingly for milk production parameters and body condition score. Of 315 cows examined, 63 individuals (20%) exhibited a ruminal pH of ≤ 5.5 at time of rumenocentesis. Of 26 farms examined, eleven farms had three or more of their cows experiencing a ruminal pH of ≤ 5.5 and were classified as likely experiencing subacute ruminal acidosis. These farms tended to be bigger than the others and offered less lying space to the lactating cows. There was no clear tendency regarding lameness. Among individual cows, animals with a low ruminal pH of ≤ 5.5 were found to be in significantly poorer body condition than animals with higher pH values (p < 0,05). The study shows 11 out of 26 of herds likely experiencing SARA. Bigger herds tend to be at a higher risk for SARA, while individuals with low ruminal pH tend to be lower in body condition. The study points to the importance of management in preventing SARA.


Physicochemical characterization and monoclonal and polyclonal antibody recognition of Baylisascaris procyonis larval excretory-secretory antigens.
Baylisascaris procyonis larval excretory-secretory (ES) antigens consisted of complex glycoproteins ranging from 10 kDa to over 200 kDa as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and lectin binding. Five monoclonal antibodies (Bapr1-Bapr5) produced against B. procyonis ES antigens were assayed by western blotting with larval ES antigens from B. procyonis, Baylisascaris melis, Baylisascaris transfuga, Ascaris suum, and Toxocara canis. Bapr1 and Bapr2 recognized periodate-sensitive epitopes on 14-kDa ES components of B. procyonis, B. melis, and B. transfuga, whereas Bapr4 and Bapr5 recognized periodate-resistant epitopes present on 55-kDa ES components of B. procyonis and B. melis. Bapr3 primarily recognized periodate-resistant epitopes on 33-45-kDa components of B. procyonis and B. melis ES. Heterologous rabbit antisera cross-reacted with many B. procyonis ES antigens on western blots, but recognition of the 33-45-kDa components was genus-specific. Normal human sera and T. canis-positive human sera also cross-reacted with many B. procyonis ES antigens, including those of 33-45 kDa. However, periodate oxidation markedly decreased cross-reactions and allowed for differential immunodiagnosis of B. procyonis versus T. canis. These studies demonstrated that antibody recognition of carbohydrate epitopes on ES components is an important cause of cross-reactions in antibody detection assays. Recognition of periodate-resistant (protein) epitopes on the 33-45-kDa B. procyonis ES components appears to be useful for genus-specific immunodiagnosis of larva migrans caused by Baylisascaris spp.


Intra-abdominal hypertension is an independent cause of postoperative renal impairment.
Intra-abdominal hypertension exerts an effect on renal function independent of other confounding variables. A prospective study of all patients admitted to an intensive care unit following abdominal surgery was undertaken between September 1, 1994, and July 31, 1997, in a single university hospital. Intra-abdominal pressure (IAP) was measured every 8 hours (normal IAP, 0-17 mm Hg); 18 mm Hg or higher was considered increased. Forward stepwise logistic regression determined whether intra-abdominal hypertension is an independent cause of renal impairment. A total of 263 patients (174 after emergency surgery), whose mean +/- SD age was 61.0 +/- 18.7 years and Acute Physiology and Chronic Health Evaluation II score was 14.6 +/- 7.7, were studied. Intra-abdominal pressure was increased in 107 (40.7%) of the 263 patients. Renal impairment occurred in 35 (32.7%) of the 107 patients with intra-abdominal hypertension and in 22 (14.1%) of the 156 with a normal IAP (odds ratio, 1.62-5.42). Using the Wald maximizing model, renal impairment was independently associated with 4 antecedent factors: hypotension (P= .09), sepsis (P = .006), age older than 60 years (P = .03), and increased IAP (P = .004). To our knowledge, for the first time in a large clinical study, IAP has been shown to be an independent cause of renal impairment, and it ranks in importance after hypotension, sepsis, and age older than 60 years. Surgeons need to be aware of the importance of intra-abdominal hypertension in patients postoperatively.


Effect of protein malnutrition on sex organs of metanil yellow exposed male rats.
Oral administration of metanil yellow (MY) at 3.0% (w/w) dose level to adult male albino rats maintained on low protein (LP) diet for 30 days resulted in a greater decrease in absolute and relative weights of testes than in those rats maintained on a normal protein (NP) diet. A marked decrease in the activities of lactate dehydrogenase and hyaluronidase and content of lactic acid in LP + MY fed animals suggested that low protein diet enhanced the vulnerability of germ cells towards metanil yellow. The lack of significant changes in the cholesterol content of testis, the fructose content of the coagulating glands and the dorso-lateral prostate, the activities of alkaline phosphatase in the seminal vesicle, and acid phosphatase in ventral prostate of the MY treated animals suggested that their androgenic status were not affected.


Nucleation theory with delayed interactions: an application to the early stages of the receptor-mediated adhesion/fusion kinetics of lipid vesicles.
A semiquantitative theory aimed to describe the adhesion kinetics between soft objects, such as living cells or vesicles, has been developed. When rigid bodies are considered, the adhesion kinetics is successfully described by the classical Derjaguin, Landau, Verwey, and Overbeek (DLVO) picture, where the energy profile of two approaching bodies is given by a two asymmetrical potential wells separated by a barrier. The transition probability from the long-distance to the short-distance minimum defines the adhesion rate. Conversely, soft bodies might follow a different pathway to reach the short-distance minimum: thermally excited fluctuations give rise to local protrusions connecting the approaching bodies. These transient adhesion sites are stabilized by short-range adhesion forces (e.g., ligand-receptor interactions between membranes brought at contact distance), while they are destabilized both by repulsive forces and by the elastic deformation energy. Above a critical area of the contact site, the adhesion forces prevail: the contact site grows in size until the complete adhesion of the two bodies inside a short-distance minimum is attained. This nucleation mechanism has been developed in the framework of a nonequilibrium Fokker-Planck picture by considering both the adhesive patch growth and dissolution processes. In addition, we also investigated the effect of the ligand-receptor pairing kinetics at the adhesion site in the time course of the patch expansion. The ratio between the ligand-receptor pairing kinetics and the expansion rate of the adhesion site is of paramount relevance in determining the overall nucleation rate. The theory enables one to self-consistently include both thermodynamics (energy barrier height) and dynamic (viscosity) parameters, giving rise in some limiting cases to simple analytical formulas. The model could be employed to rationalize fusion kinetics between vesicles, provided the short-range adhesion transition is the rate-limiting step to the whole adhesion process. Approximate relationships between the experimental fusion rates reported in the literature and parameters such as membrane elastic bending modulus, repulsion strength, temperature, osmotic forces, ligand-receptor binding energy, solvent and membrane viscosities are satisfactory explained by our model. The present results hint a possible role of the initial long-distance-->short-distance transition in determining the whole fusion kinetics.


[Influence of general practitioners' personal knowledge on migraine in medical attitudes towards their patients suffering from migraine].
The subjective aspects of the doctor-patient relationship may impact disease management methods applied to migraine patients. This prospective study compared the medical attitudes of doctors towards migraine headache in relationship to their personal sensitivity to this disease. The study concerned data on the health care management of migraine headache by 711 general practitioners, 325 of whom suffer from migraine headache themselves, 227 who do not suffer from migraines, but who have a close family member that does, and 159 who neither suffer from migraine headache, nor have anyone close who does. Each doctor filled out a medical practice questionnaire concerning this pathology and included one migraine patient in the survey. Each patient answered a specific quality of life questionnaire. It was shown that doctors suffering from migraine headache themselves declared having more migraine patients in their practices than the other doctors. Nonetheless, the doctor's sensitivity to migraine headache does not seem to have an impact on the diagnosis and therapeutic care of patients; diagnosis criteria are the same within the three groups and correspond to international headache society criteria. Furthermore, the therapeutic means applied, whether acute first or second intention treatment, or long-term treatment, do not differ amongst the three groups. Quality of life and patients' feelings about medical support were significantly related to the doctor's level of sensitivity towards the disease: they were highest amongst patients treated by doctors suffering from migraines themselves, and lowest amongst patients treated by doctors with no close family members suffering from migraines. Although therapeutical attitudes do not vary, the quality of life perceived by patients is better when the doctors themselves are concerned by the disease.


Curbside Collection of Recyclable Material: Simulation of Collection Activities and Estimation of Vehicle and Labor Needs.
This paper presents a mathematical model that can be used to estimate the time required to collect recyclable material (route time) by simulating the activities of a collection vehicle driving over its route. Data obtained by observing the collection of recyclable material in The Village, OK, were used to determine parameters for the model. The validity and robustness of the model were tested by comparing model-predicted route time to observed route time. The model was able to predict route time within 8%. Simulation procedures are presented that can be used to estimate route time under conditions not actually ob-served-for instance, very low or high rates of material being set out for collection. The simulation procedures, incorporating randomly assigned set-out distributions, indicate that set-out distribution (proximity of houses setting out materials) has little effect on route time. Vehicle and labor needs for the curbside collection of recyclable material in a hypothetical town are estimated to demonstrate a practical application of the simulation procedure. The results indicate that if set-out rate were to increase from 20% to 30%, labor needs would increase by 34% and an additional vehicle would be needed to serve the same number of households. Increasing set-out rate from 20% to 40% would result in a labor requirement increase of 68%. Calculations such as these are particularly significant if a program to increase participation is being considered.


Management of hearing impairment in the Canadian Inuit--an update.
In recent years, the teachers in the north and the Inuit have become increasingly aware of the educational effects of hearing los frequently associated with chronic otitis media. In the Baffin Zone, N.W.T. and in Nouveau Quebec a surge of enthusiasm has surfaced to do something positive and on-going about the problem. A description of events and changes in attitude occurring among the Inuit, educators, and medical services is presented.


Synthesis and Utilization of Nitroalkyne Equivalents in Batch and Continuous Flow.
We report a method for overcoming the low stability of nitroalkynes through the development of nitrated vinyl silyltriflate equivalents. Because of their instability, nitroalkynes have only rarely been utilized in synthesis. The reactivity of these silyltriflates, which are prepared in situ, is exemplified by dipolar cycloaddition reactions with nitrones to give highly substituted 4-nitro-4-isoxazolines in high yields. This approach has proven general for several different alkyl and aryl substituted alkynes. In order to minimize the accumulation of potentially hazardous reaction intermediates, we have also developed a continuous flow variant of this method that is capable of carrying out the entire reaction sequence in a good yield and a short residence time.


Importance of Early Detection and Cardiovascular Surgical Intervention in Marfan Syndrome.
Marfan syndrome is an autosomal dominant connective tissue disorder that affects multiple systems, including the skeletal, ligamentous, oculofacial, pulmonary, abdominal, neurological, and cardiovascular systems. Cardiovascular complications, which involve the aorta and aortic valve, contribute most significantly to patient morbidity and mortality. A literature review was conducted on pathophysiology of the disease and recommendations for early diagnosis and treatment. Diagnosis largely relies on clinical features and a thorough history. Echocardiogram is used for monitoring aortic abnormalities and disease progression. Aortic valve-sparing surgery is indicated in any valvular abnormality and in patients with a murmur. Aortic root replacement is indicated prophylactically in women who want to give birth with diameters greater than 40 mm, anyone with a diameter greater than 50 mm, and progressive dilatation of greater than 5 mm per year. Medical management involves antihypertensive therapy. It is imperative for all health care providers to understand the clinical features, progression, and management of Marfan syndrome to appropriately care for their patients. Ensuring regular follow-up and adherence to medical and surgical prophylaxis is essential to patient well-being.


The role of phosphodiesterase activity on the temperature-dependent responses of calf cardiac vein.
To evaluate the role of phosphodiesterase (PDE) activity in the cooling (to 28 °C) and warming (41 °C)-induced effects of carbachol on calf cardiac vein. Rings obtained from calf hearts were suspended in organ baths containing 25 ml of Krebs-Henseleit solution, maintained at 37 °C, continuously gassed with 95%O2-5%CO2. At the end of the resting period the preparations were contracted with carbachol (10-9-3x10-4M), at 37 °C. The same protocol was repeated at 28 °C and 41 °C after the preparations were allowed to equilibrate at this temperature for 60 min. In order to analyze the role of PDE activity in the cooling-and warming-induced vascular response, carbachol (10-9-3x10-4M) was applied in the presence of cilostazol (10-6 M), IBMX (10-6 M) and rolipram (10-6 M), respectively. The sensitivity of carbachol was significantly lower during cooling, and higher during warming. Cooling to 28 and warming to 41 °C, after treatment with IBMX, cilostazol or rolipram, significantly decreased the sensitivity to carbachol (p<0.05). The results of the present study suggest that PDE activity plays an essential role in cooling-and warming-induced changes of calf cardiac vein treated with carbachol (Tab. 1, Fig. 2, Ref. 34). Text in PDF www.elis.sk.


Correlates of Occurrence of Obstetric Fistula among Women in Selected States of India: An Analysis of DLHS-3 Data.
Obstetric fistula is the most devastating form of maternal morbidity. It is an opening in the wall of vagina connecting to bladder or to rectum due to prolonged obstructed labour without timely medical assistance. A few research studies carried out in India and recently conducted DLHS-3 survey (2007-08) has information on obstetric fistula that gives scope for further research. This paper examines prevalence of obstetric fistula and its correlates using DLHS-3 data for selected states in India. Ever experience of obstetric fistula among women in these states ranges from 0.3 percent to 3.4 percent, being highest in Uttarakhand. Women living in rural areas have higher chance of obstetric fistula. Age and physical maturity is important factor in the occurrence of fistula and it is found that those women who were below 18 years at the time of their first birth have higher risk of fistula in comparison to those who had child at 18 or above years. In addition to this, those having problems at the time of delivery are around two times more likely to have fistula. Auxulary Nurse Midwife can be key players in the early detection and referral of cephalo-pelvic disproportion, malpresentation and prolonged, obstructed labour cases.


Ligand Crosslinking Boosts Thermal Transport in Colloidal Nanocrystal Solids.
The ongoing interest in colloidal nanocrystal solids for electronic and photonic devices necessitates that their thermal-transport properties be well understood because heat dissipation frequently limits performance in these devices. Unfortunately, colloidal nanocrystal solids generally possess very low thermal conductivities. This very low thermal conductivity primarily results from the weak van der Waals interaction between the ligands of adjacent nanocrystals. We overcome this thermal-transport bottleneck by crosslinking the ligands to exchange a weak van der Waals interaction with a strong covalent bond. We obtain thermal conductivities of up to 1.7 Wm-1 K-1 that exceed prior reported values by a factor of 4. This improvement is significant because the entire range of prior reported values themselves only span a factor of 4 (i.e., 0.1-0.4 Wm-1 K-1 ). We complement our thermal-conductivity measurements with mechanical nanoindentation measurements that demonstrate ligand crosslinking increases Young's modulus and sound velocity. This increase in sound velocity is a key bridge between mechanical and thermal properties because sound velocity and thermal conductivity are linearly proportional according to kinetic theory. Control experiments with non-crosslinkable ligands, as well as transport modeling, further confirm that ligand crosslinking boosts thermal transport.


Histone deacetylase HDA710 controls salt tolerance by regulating ABA signaling in rice.
Plants have evolved numerous mechanisms that assist them in withstanding environmental stresses. Histone deacetylases (HDACs) play crucial roles in plant stress responses; however, their regulatory mechanisms remain poorly understood. Here, we explored the function of HDA710/OsHDAC2, a member of the HDAC RPD3/HDA1 family, in stress tolerance in rice (Oryza sativa). We established that HDA710 localizes to both the nucleus and cytoplasm and is involved in regulating the acetylation of histone H3 and H4, specifically targeting H4K5 and H4K16 under normal conditions. HDA710 transcript accumulation levels were strongly induced by abiotic stresses including drought and salinity, as well as by the phytohormones jasmonic acid (JA) and abscisic acid (ABA). hda710 knockout mutant plants showed enhanced salinity tolerance and reduced ABA sensitivity, whereas transgenic plants overexpressing HDA710 displayed the opposite phenotypes. Moreover, ABA- and salt-stress-responsive genes, such as OsLEA3, OsABI5, OsbZIP72, and OsNHX1, were upregulated in hda710 compared with wild-type plants. These expression differences corresponded with higher levels of histone H4 acetylation in gene promoter regions in hda710 compared with the wild type under ABA and salt-stress treatment. Collectively, these results suggest that HDA710 is involved in regulating ABA- and salt-stress-responsive genes by altering H4 acetylation levels in their promoters. This article is protected by copyright. All rights reserved.


Isoorientin Ameliorates APAP-Induced Hepatotoxicity via Activation Nrf2 Antioxidative Pathway: The Involvement of AMPK/Akt/GSK3β.
Oxidative stress has been highlighted as therapeutic targets for acetaminophen (APAP)-induced hepatotoxicity. Isoorientin (Iso), a well-known flavonoid-like compound, has been shown to have antioxidant potential. However, the effect of Iso on APAP-induced liver injury has not yet been elucidated. The present study investigated the hepatoprotective effect of Iso and its underlying mechanism. C57BL/6J mice were used to evaluate the hepatoprotective effect of Iso in vivo and HepG2 cells were utilized to further decipher the mechanisms of Iso -induced Nrf2 activation. We found that Iso treatment significantly reduced APAP-induced hepatotoxicity by reducing the lethality, histopathological liver changes, and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum. These effects were accompanied by decreased malondialdehyde (MDA) formation and myeloperoxidase level (MPO), and by decreased superoxide dismutase (SOD) and glutathione (GSH) depletion. Moreover, Iso induced Nrf2 activation and translocation as well as upstream AMPK/Akt/GSK3β activation. Furthermore, Iso effectively alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, Bax mitochondrial translocation, and apoptosis-inducing factor and cytochrome c release. Further mechanistic investigations revealed that the activation of Nrf2 by Iso via the AMPK/Akt/GSK3β pathway contributed to the hepatoprotective activity of Iso in vitro. In addition, the Iso-mediated inhibition of APAP-induced the lethality, histopathological changes and mitochondrial dysfunction observed in WT mice was nearly absent in Nrf2-/- mice. In summary, Iso ameliorated APAP-induced hepatotoxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.