Hepatitis E virus epidemiology in industrialized countries.
To determine the prevalence of Hepatitis E virus (HEV) in industrialized nations, we analyzed the excretion of HEV strains by the populations of Spain, France, Greece, Sweden, and the United States. Twenty of 46 (43.5%) urban sewage samples collected in Barcelona from 1994 to 2002 tested positive for HEV. We identified 15 HEV strains, which were similar to two HEV isolates previously described in Barcelona in clinical samples and to strains from diverse geographic HEV-nonendemic areas. We also identified two HEV strains in sewage samples from Washington, D.C., and Nancy, France; these samples were also positive for Hepatitis A virus. In addition, we studied the role of pigs as a reservoir for HEV and identified one new swine HEV strain. Our results suggest that HEV may be more prevalent than previously considered in industrialized countries and that variants of the virus circulate simultaneously in one region.


[Causes of death and errors in the therapy of patients with strangulated hernias].
Among a group of 2,060 patients who underwent operation for strangulated abdominal hernias, 127 (6.2%) died. Analysis of the fatal outcomes showed that factors causing a negative effect on the results of treatment are essentially homogeneous. These included: a high proportion of elderly patients, late hospitalization, and the doctors' therapeutic and diagnostic errors. The percentage of the latter in the in-patient clinic is quite high (20.5). Immediate hospitalization of patients with a strangulated hernia and skilled operative treatment, as well as planned preventive management of individuals with hernia, are still the main reserve in improving the results of treatment of this pathological condition.


Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders.
Methylation of histone H3 lysine 4 (H3K4me) is an intricately regulated posttranslational modification, which is broadly associated with enhancers and promoters of actively transcribed genomic loci. Recent advances in next-generation sequencing have identified a number of H3K4me regulators mutated in neurodevelopmental disorders including intellectual disabilities, autism spectrum disorders, and schizophrenia. Here, we aim to summarize the molecular function of H3K4me-regulating enzymes in brain development and function. We describe four H3K4me methyltransferases (KMT2A, KMT2C, KMT2D, KMT2F), four demethylases (KDM1A, KDM5A, KDM5B, KDM5C), and two reader proteins (PHF21A, PHF8) mutated in neurodevelopmental disorders. Understanding the role of these chromatin regulators in the development and maintenance of neural connections will advance therapeutic opportunities for prevention and treatment of these lifelong neurodevelopmental disorders.


Do farmers value rice varieties tolerant to droughts and floods? Evidence from a discrete choice experiment in Odisha, India.
Abiotic stresses such as droughts and floods significantly constrain rice production in India. New stress tolerant technologies have the potential to reduce yield variability and help insulate farmers from the risks posed by these hazards. Using discrete choice experiments conducted in rural Odisha, we estimate farmers' valuation for drought-tolerant (DT) and submergence-tolerant (SubT) traits embodied in rice cultivars. Our results demonstrate that farmers in both drought-prone as well as submergence prone regions value reduction in yield variability offered by new, stress-tolerant cultivars, and would generally be willing to pay a significant premium for these traits. While virtually all farmers perceive the threat of drought and are willing to pay for protection against drought risk, only farmers in flood-prone areas would be willing to pay for rice that can withstand being submerged for prolonged periods, suggesting the potential for market segmentation along geographical or ecological lines.


An impaired peroxisomal targeting sequence leading to an unusual bicompartmental distribution of cytosolic epoxide hydrolase.
To gain an understanding of the mechanism by which the subcellular distribution of cytosolic epoxide hydrolase (cEH) is directed, we have analyzed the carboxy terminal region of rat liver cEH by means of cDNA cloning to define the structure of its possible peroxisomal targeting sequence (PTS). Purified cEH was subjected to peptide analysis following endoproteinase Glu-C digestion and HPLC-separation of the fragments. The obtained sequence information was used to perform PCR experiments resulting in the isolation of a 680 bp cDNA clone encoding the carboxy terminus of cEH. The deduced amino acid sequence displays a terminal tripeptide Ser-Lys-Ile which is highly homologous to the PTS (Ser-Lys-Leu) found in other peroxisomal enzymes. This slight difference appears to be sufficient to convert the signal sequence into an impaired and therefore ambivalent PTS, directing the enzyme partly to the peroxisomes and allowing part to reside in the cytosol.


Purification and physical characterization of glutathione S-transferase K. Differential use of S-hexylglutathione and glutathione affinity matrices to isolate a novel glutathione S-transferase from rat liver.
A novel hepatic enzyme, glutathione S-transferase K, is described that, unlike previously characterized transferases, possesses little affinity for S-hexylglutathione-Sepharose 6B but can be isolated because it binds to a glutathione affinity matrix. A purification scheme for this new enzyme was devised, with the use of DEAE-cellulose, S-hexylglutathione-Sepharose 6B, glutathione-Sepharose 6B and hydroxyapatite chromatography. The final hydroxyapatite step results in the elution of three chromatographically interconvertible forms, K1, K2 and K3. The purified protein has an isoelectric point of 6.1 and comprises subunits that are designated Yk (Mr 25,000); during sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, it migrates marginally faster than the Ya subunit but slower than the pulmonary Yf monomer (Mr 24,500). Transferase K displays catalytic, immunochemical and physical properties that are distinct from those of other liver transferases. Tryptic peptide maps suggest that transferase K is a homodimer, or comprises closely homologous subunits. The tryptic fingerprints also demonstrate that, although transferase K is structurally separate from previously described hepatic forms, a limited sequence homology exists between the Yk, Ya and Yc polypeptides. These structural data are in accord with the immunochemical results presented in the accompanying paper [Hayes & Mantle (1986) Biochem. J. 233, 779-788].


Extracellular Mg concentration and Ca blockers modulate the initial steps of the response of Th2 lymphocytes in co-culture with macrophages and dendritic cells.
Magnesium is highly involved in the metabolic network such that even subtle disturbances in its homeostasis affect many cellular functions, including calcium homeostasis, signal transduction, energy metabolism, membrane stability and cell proliferation. Recently, magnesium level has been proposed to modulate the priming and activity of immune cells. We studied the behavior of antigen-presenting cells (APCs) and T lymphocytes after altering the magnesium/calcium balance. We used two different populations of primary APCs, i.e. bone marrow-derived dendritic cells and bone marrow-derived macrophages, while D10.G4.1 cells served as a model of responding Th2 cells. Our principal findings are the following: (i) the extracellular magnesium concentration had no significant impact on endocytosis by bone marrow-derived APCs, (ii) high concentrations of extracellular magnesium, with or without calcium antagonists, significantly decreased IL-4 and IL-10 secretion by Th2 cells in a co-culture system of APCs and Th2 lymphocytes, (iii) proliferation of Th2 cells in co-culture systems was significantly inhibited by calcium antagonists independently from extracellular magnesium concentrations. Our results suggest that alterations of magnesium and calcium homeostasis impact on some crucial steps of the immune response.


Evidence-based medicine and rapid response team implementation.
The implementation of Rapid Response Teams is becoming commonplace in U.S. hospitals, following the model developed in Australia. The Rapid Response Team is a method of bringing ICU-level patient care to the bedside of critically ill patients using a multidisciplinary team. Acute care unit staff are trained to recognize clinical deterioration using a set of vital sign calling criteria (systolic blood pressure below 90 mmHg, pulse below 60 or above 100, etc.). Many hospitals have been facing problems gaining needed support to make the organizational changes needed for the team to function properly. Some faculty physicians have expressed apprehension about losing control over their patients, and they have also highlighted the lack of rigorous experimental evidence that the teams work. Since there are so many confounding factors at work when trying to design an experimental study of this type of change, the study may not accurately portray the situation. Other evaluation methods should therefore be considered.


Correlation Between Circulating Tumor DNA Levels and Response to Tyrosine Kinase Inhibitors (TKI) Treatment in Non-Small Cell Lung Cancer.
BACKGROUND Clinical monitoring of EGFR-positive NSCLC patients is important to gauge treatment response. The current study addresses the usage of circulating tumor DNA (ctDNA) as a prognostic marker during treatment of first-generation TKIs. MATERIAL AND METHODS Serial samplings of peripheral blood from 200 EGFR-positive NSCLC patients were taken. Baseline ctDNA quantification was conducted by digital droplet PCR before TKI treatment was administered and compared to primary biopsies. Thereafter blood sampling at different treatment cycles were measured and assessed for its prognostic and predictive value. RESULTS ctDNA was successfully detected in a number of patients and overall concordance rate was 84%. Importantly, we observed a strong correlation to ctDNA increase with disease progression using radiographic scans. In addition to survival analysis, we noted patients with the largest ctDNA variations had worst outcome. A significant number of EGFR patients during treatment developed a secondary mutation T790M and this cohort had worst survival outcome as well. CONCLUSIONS Our study demonstrated a highly associative relation of ctDNA to NSCLC patients during treatment that can be utilized to gauge treatment response. CtDNA is an attractive means compared with conventional core needle biopsies and presents new methods for accurately profiling NSCLC disease progression.


Interleukin-8 (IL-8) is a major neutrophil chemotaxin from human alveolar macrophages stimulated with staphylococcal enterotoxin A (SEA).
Since Staphylococcus aureus is an important human pathogen, and infection of the lungs is characterized by neutrophil infiltration we studied the role of a staphylococcal toxin, enterotoxin A (SEA) on the synthesis and secretion of IL-8 by human alveolar macrophages. As SEA concentration was increased, the IL-8 accumulation in the macrophage conditioned medium increased. The concentration of mRNA encoding IL-8 was also elevated in the macrophage in response to increases in SEA concentration. Although the monocytic cell line U937 was able to respond to SEA and secrete IL-8, treatment with PMA prior to SEA stimulation increased the IL-8 accumulation around fifty fold indicating that maturation of the undifferentiated cell to a more macrophage-like cell facilitated IL-8 accumulation. Stimulating human alveolar macrophages with high concentrations of SEA caused an increase in IL-1 accumulation. However, when the cells were incubated with SEA in the presence of IL-1 receptor antagonist, there was no decrease in IL-8 accumulation. Addition of a neutralizing anti-IL-8 monoclonal antibody to the culture medium of SEA-stimulated macrophages significantly reduced the neutrophil chemotactic activity of the medium. These studies showed that IL-8 is a major neutrophil chemotaxin from human alveolar macrophages stimulated with SEA.


Spinal Cord Injury in the Geriatric Population: Risk Factors, Treatment Options, and Long-Term Management.
Spinal cord injuries (SCIs) are sustained by more than 12 500 patients per year in the United States and more globally. The SCIs disproportionately affect the elderly, especially men. Approximately 60% of these injuries are sustained traumatically through falls, but nontraumatic causes including infections, tumors, and medication-related epidural bleeding have also been documented. Preexisting conditions such as ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis can render the spine stiff and are risk factors as well as cervical spondylosis and ensuing cervical stenosis. Treatment options vary depending on the severity, location, and complexity of the injury. Surgical management has been growing in popularity over the years and remains an option as it helps reduce spinal cord compression and alleviate pain. Elevating mean arterial pressures to prevent spinal cord ischemia and avoiding the second hit of SCI have become more common as opposed to high dose steroids. Ongoing clinical trials with pharmacological agents such as minocycline and riluzole have shown early, promising results in their ability to reduce cellular damage and facilitate recovery. Though SCI can be life changing, the available treatment options have aimed to reduce pain and minimize complications and maintain quality of life alongside rehabilitative services.


Incorporation of silver nanoparticles into magnetron-sputtered calcium phosphate layers on titanium as an antibacterial coating.
A three-layer system of nanocrystalline hydroxyapatite (first layer; 1000nm thick), silver nanoparticles (second layer; 1.5μg Ag cm-2) and calcium phosphate (third layer, either 150 or 1000nm thick) on titanium was prepared by a combination of electrophoretic deposition of silver nanoparticles and the deposition of calcium phosphate by radio frequency magnetron sputtering. Scanning electron microscopy showed that the silver nanoparticles were evenly distributed over the surface. The adhesion of multilayered coating on the substrate was evaluated using the scratch test method. The resistance to cracking and delamination indicated that the multilayered coating has good resistance to contact damage. The release of silver ions from the hydroxyapatite/silver nanoparticle/calcium phosphate system into the phosphate-buffered saline (PBS) solution was measured by atomic absorption spectroscopy (AAS). Approximately one-third of the incorporated silver was released after 3days immersion into PBS, indicating a total release time of the order of weeks. There were no signs of cracks on the surface of the coating after immersion after various periods, indicating the excellent mechanical stability of the multilayered coating in the physiological environment. An antimicrobial effect against Escherichia coli was found for a 150nm thick outer layer of the calcium phosphate using a semi-quantitative turbidity test.


Incidence of white spot lesions among patients treated with clear aligners and traditional braces.
To compare the incidence of white spot lesions (WSLs) among patients treated with aligners and those treated with traditional braces. A group of 244 aligner patients (30.4 ± 14 years) was compared to a group of 206 patients (29.2 ± 11.5 years) treated with traditional fixed braces. Consecutive cases in the late mixed or permanent dentitions who had high-quality pre- and posttreatment digital photographs available were included in the study. Each set of photographs was independently evaluated by two investigators to determine pretreatment oral hygiene (OH), fluorosis, and WSLs, as well as changes in OH and WSLs during treatment. Approximately 1.2% of the aligner patients developed WSLs, compared to 26% of the traditionally treated patients. The numbers of WSLs that developed were also significantly (P < .001) less among the aligner patients. The aligner patients developed three new WSLs, while the traditionally treated patients developed 174 WSLs. The incidence of WSLs was greater for the maxillary than for the mandibular teeth, and it was greater for the canines than for the incisors. For the patients treated with traditional braces, fair or poor pretreatment OH, worsening of OH during treatment, preexisting WSLs, and longer treatment duration significantly (P < .05) increased the risk of developing WSLs during treatment. Patients treated with aligners have less risk of developing WSLs than do patients treated with traditional braces, which could be partially due to shorter treatment duration, or better pretreatment OH.


Ventilatory management of respiratory failure in patients with severe Guillain-Barre syndrome.
Guillain-Barre syndrome (GBS) is the commonest peripheral neuropathy causing ventilatory failure, and 10-30% patients may require respiratory support. Records of 11 adult patients of GBS in respiratory failure, admitted to the Respiratory Intensive Care Unit (RICU) of our institute for mechanical ventilation over a four-year period, were studied. Six patients received intravenous immunoglobulin. The median duration of mechanical ventilation was 38 days. Seven patients underwent tracheostomy. Four patients were ventilated for less than 2 weeks and 3 for more than 2 months each. Seven developed ventilator-associated pneumonia and/or sepsis. Three patients died in, and two shortly after discharge from RICU; all had systemic problems or complications of hospitalization.


Induction of nuclear envelope breakdown, chromosome condensation, and spindle formation in cell-free extracts.
Incubation of demembranated sperm chromatin in cytoplasmic extracts of unfertilized Xenopus laevis eggs resulted in nuclear envelope assembly, chromosome decondensation, and sperm pronuclear formation. In contrast, egg extracts made with EGTA-containing buffers induced the sperm chromatin to form chromosomes or irregularly shaped clumps of chromatin that were incorporated into bipolar or multipolar spindles. The 150,000 g supernatants of the EGTA extracts could not alone support these changes in incubated nuclei. However, these supernatants induced not only chromosome condensation and spindle formation, but also nuclear envelope breakdown when added to sperm pronuclei or isolated Xenopus liver or brain nuclei that were incubated in extracts made without EGTA. Similar changes were induced by partially purified preparations of maturation-promoting factor. The addition of calcium chloride to extracts containing condensed chromosomes and spindles caused dissolution of the spindles, decondensation of the chromosomes, and re-formation of interphase nuclei. These results indicate that nuclear envelope breakdown, chromosome condensation, and spindle assembly, as well as the regulation of these processes by Ca2+-sensitive cytoplasmic components, can be studied in vitro using extracts of amphibian eggs.


An experimental study on the effects of peer drinking norms on adolescents' drinker prototypes.
Adolescents form impressions about the type of peers who drink (i.e., drinker prototypes). The evaluation of, and perceived similarity to these prototypes are related to adolescents' drinking. Peer drinking norms play an important role in the formation of prototypes. We experimentally examined whether manipulation of peer norms changed the evaluation of and perceived similarity to drinker prototypes and whether these changes were moderated by peers' popularity. In a pre-test, we assessed heavy drinker, moderate drinker and abstainer prototypes, drinking behaviors and peer-perceived popularity among 599 adolescents. Additionally, 88 boys from this sample participated in a simulated chat room, in which they interacted with peers from school. These peers were in fact pre-programmed e-confederates, who were either popular or unpopular and who communicated either pro-alcohol or anti-alcohol norms. After the chat room interaction we assessed participants' drinker prototypes. Participants exposed to anti-alcohol norms were more negative about, and perceived themselves as less similar to heavy drinker prototypes, than participants exposed to pro-alcohol norms. We found no effects of peer norms on moderate drinker and abstainer prototypes. Effects were not moderated by peers' popularity. We did find a main effect of popularity on perceived similarity to all prototypes. This indicated that participants rated themselves as more similar to heavy and moderate drinker prototypes and less similar to abstainer prototypes when they interacted with unpopular peers than with popular peers. Exposure to anti-alcohol norms of peers leads adolescents to form more negative prototypes of the heavy drinker. This could be an important finding for prevention and intervention programs aimed to reduce alcohol consumption among adolescents.


Fluoxetine treatment of children and adults with autistic disorder and mental retardation.
An open trial of pharmacological treatment with fluoxetine, ranging from 20 mg every other day to 80 mg per day, led to a significant improvement in Clinical Global Impressions ratings of Clinical Severity in 15 of 23 subjects with autistic disorder and 10 of 16 subjects with mental retardation. Six of 23 patients with autistic disorder and 3 of 16 patients with mental retardation had side effects which significantly interfered with function, consisting predominantly of restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Double-blind studies of the efficacy of pharmacological agents that potently inhibit 5-HT uptake in the treatment of mental retardation coexisting with Axis I psychiatric disorders (especially obsessive-compulsive disorder) and autistic disorder are warranted.


[Genetic control of riboflavin biosynthesis in Pichia guilliermondii yeasts. The detection of a new regulator gene RIB81].
The properties of mutants resistant to 7-methyl-8-trifluoromethyl-10-(1'-D-ribityl)-isoalloxazine (MTRY) were studied. The mutants were isolated from a genetic line of Pichia guilliermondii. Several of them were riboflavin overproducers and had derepressed flavinogenesis enzymes (GTP cyclohydrolase, 6.7-dimethyl-8-ribityllumazine synthase) in iron-rich medium. An additional derepression of these enzymes as well as derepression of riboflavin synthase occurred in iron-deficient medium. The characters "riboflavin oversynthesis" and "derepression of enzymes" were recessive in mutants of the 1st class, or dominant in those of the 2nd class. The hybrids of analogue-resistant strains of the 1st class with previously isolated regulatory mutants ribR (novel designation rib80) possessed the wild-type phenotype and were only capable of riboflavin overproduction under iron deficiency. Complementation analysis of the MTRY-resistant mutants showed that vitamin B2 oversynthesis and enzymes' derepression in these mutants are caused by impairment of a novel regulatory gene, RIB81. Thus, riboflavin biosynthesis in P. guilliermondii yeast is regulated at least by two genes of the negative action: RIB80 and RIB81. The meiotic segregants which contained rib80 and rib81 mutations did not show additivity in the action of the above regulatory genes. The hybrids of rib81 mutants with natural nonflavinogenic strain P. guilliermondii NF1453-1 were not capable of riboflavin oversythesis in the iron-rich medium. Apparently, the strain NF1453-1 contains an unaltered gene RIB81.


[Ways of indication rise for operation in elderly and senile aged patients with stomach cancer].
An article presents an analysis of treatment of 113 patients (aged from 60 to 91 years old) with stomach cancer. On this basis, an algorithm of examination of given age group was developed. Preoperative diagnostics wasn't directed only to an establishment of prevalence, a stage of main process. At the same time, it was aimed to determination and correction of accompanying somatic pathology, which required an application of multidisciplinary approach. An echocardiography was used for a functional condition assessment of cardiovascular and respiratory systems. The strategy allowed the indication rise for operation up to 96.5% in given group of patients.


Cloning and expression in Escherichia coli of isopenicillin N synthetase genes from Streptomyces lipmanii and Aspergillus nidulans.
beta-Lactam antibiotics such as penicillins and cephalosporins are synthesized by a wide variety of microbes, including procaryotes and eucaryotes. Isopenicillin N synthetase catalyzes a key reaction in the biosynthetic pathway of penicillins and cephalosporins. The genes encoding this protein have previously been cloned from the filamentous fungi Cephalosporium acremonium and Penicillium chrysogenum and characterized. We have extended our analysis to the isopenicillin N synthetase genes from the fungus Aspergillus nidulans and the gram-positive procaryote Streptomyces lipmanii. The isopenicillin N synthetase genes from these organisms have been cloned and sequenced, and the proteins encoded by the open reading frames were expressed in Escherichia coli. Active isopenicillin N synthetase enzyme was recovered from extracts of E. coli cells prepared from cells containing each of the genes in expression vectors. The four isopenicillin N synthetase genes studied are closely related. Pairwise comparison of the DNA sequences showed between 62.5 and 75.7% identity; comparison of the predicted amino acid sequences showed between 53.9 and 80.6% identity. The close homology of the procaryotic and eucaryotic isopenicillin N synthetase genes suggests horizontal transfer of the genes during evolution.


Neglected Venomous Animals and Toxins: Underrated Biotechnological Tools in Drug Development.
Among the vast repertoire of animal toxins and venoms selected by nature and evolution, mankind opted to devote its scientific attention-during the last century-to a restricted group of animals, leaving a myriad of toxic creatures aside. There are several underlying and justifiable reasons for this, which include dealing with the public health problems caused by envenoming by such animals. However, these studies became saturated and gave rise to a whole group of animals that become neglected regarding their venoms and secretions. This repertoire of unexplored toxins and venoms bears biotechnological potential, including the development of new technologies, therapeutic agents and diagnostic tools and must, therefore, be assessed. In this review, we will approach such topics through an interconnected historical and scientific perspective that will bring up the major discoveries and innovations in toxinology, achieved by researchers from the Butantan Institute and others, and describe some of the major research outcomes from the study of these neglected animals.


Modeling of a type II photofrin-mediated photodynamic therapy process in a heterogeneous tissue phantom.
We present a quantitative framework to model a Type II photodynamic therapy (PDT) process in the time domain in which a set of rate equations are solved to describe molecular reactions. Calculation of steady-state light distributions using a Monte Carlo method in a heterogeneous tissue phantom model demonstrates that the photon density differs significantly in a superficial tumor of only 3 mm thickness. The time dependences of the photosensitizer, oxygen and intracellular unoxidized receptor concentrations were obtained and monotonic decreases in the concentrations of the ground-state photosensitizer and receptor were observed. By defining respective decay times, we quantitatively studied the effects of photon density, drug dose and oxygen concentration on photobleaching and cytotoxicity of a photofrin-mediated PDT process. Comparison of the dependences of the receptor decay time on photon density and drug dose at different concentrations of oxygen clearly shows an oxygen threshold under which the receptor concentration remains constant or PDT exhibits no cytotoxicity. Furthermore, the dependence of the photosensitizer and receptor decay times on the drug dose and photon density suggests the possibility of PDT improvement by maximizing cytotoxicity in a tumor with optimized light and drug doses. We also discuss the utility of this model toward the understanding of clinical PDT treatment of chest wall recurrence of breast carcinoma.


Facilitating Clinical Outcomes Assessment through the automated identification of quality measures for prostate cancer surgery.
The College of American Pathologists (CAP) Category 1 quality measures, tumor stage, Gleason score, and surgical margin status, are used by physicians and cancer registrars to categorize patients into groups for clinical trials and treatment planning. This study was conducted to evaluate the effectiveness of an application designed to automatically extract these quality measures from the postoperative pathology reports of patients having undergone prostatectomies for treatment of prostate cancer. An application was developed with the Clinical Outcomes Assessment Toolkit that uses an information pipeline of regular expressions and support vector machines to extract CAP Category 1 quality measures. System performance was evaluated against a gold standard of 676 pathology reports from the University of California at Los Angeles Medical Center and Brigham and Women's Hospital. To evaluate the feasibility of clinical implementation, all pathology reports were gathered using administrative codes with no manual preprocessing of the data performed. The sensitivity, specificity, and overall accuracy of system performance were measured for all three quality measures. Performance at both hospitals was compared, and a detailed failure analysis was conducted to identify errors caused by poor data quality versus system shortcomings. Accuracies for Gleason score were 99.7%, tumor stage 99.1%, and margin status 97.2%, for an overall accuracy of 98.67%. System performance on data from both hospitals was comparable. Poor clinical data quality led to a decrease in overall accuracy of only 0.3% but accounted for 25.9% of the total errors. Despite differences in document format and pathologists' reporting styles, strong system performance indicates the potential of using a combination of regular expressions and support vector machines to automatically extract CAP Category 1 quality measures from postoperative prostate cancer pathology reports.


Urine Metabolites and Antioxidant Effect after Oral Intake of Date (Phoenix dactylifera L.) Seeds-Based Products (Powder, Bread and Extract) by Human.
A cross-over study was conducted in 16 healthy adult volunteers to describe the urinary excretion of polyphenols from date seeds and investigate the antioxidant effect after consumption of different doses of date seeds powder (DSP), bread (DSB) and extract (DSE). After 12 h of fasting, one of the six treatments (0.25 g and 0.5 g/kg bodyweight DSP, 360 g of 10% and 15% DSB, 30 mg and 60 mg/kg bodyweight DSE) was provided along with breakfast, with a two weeks wash-out period between 2 consecutive treatments. Blood was drawn at baseline, 1, 2, 8 and 24 h post intake. Urine was collected at baseline, 3, 8, and 24 h post intake. An abundant release of polyphenols was detected in urine within the 0-3 h post intake, reached a peak at 8 h, then decreased with polyphenols still being detected up to 24 h post intake. The antioxidant defence system, as measured by reduced glutathione (GSH), was strengthened as soon as 1 h and up to 8 h post intake. Markers of protein and lipid oxidative damages were reduced from 1 h and up to 8 and 24 h post intake, respectively. This supports an antioxidant effect of date seeds products in humans, most probably due to their polyphenols.


Fuel prices and road deaths: Motorcyclists are different.
This study estimates the effect of gasoline prices on road deaths by vehicle mode using annual data for 62 countries for 2000-2018 and all states of the United States (US) for 1998-2018. Higher gasoline prices are associated with fewer overall road deaths. The proportional effect on motorcyclist deaths tends to be smaller or even have the opposite sign, especially in countries that are not highly dependent on motorcycles. For the US, a positive effect of gasoline prices on motorcyclist deaths is found, with an elasticity of about 0.3. There is also a positive relationship between gasoline prices and motorcycle registrations in the US. The results confirm that additional attention towards motorcyclist safety is warranted in times of high fuel prices.


The immunology ecosystem in South Africa: striking an equitable balance between fostering discovery, promoting translation and capacity building.
In the vast and diverse continent of Africa, the field of immunology holds immense significance as it navigates the complex landscape of infectious diseases and public health challenges. In this article, we speak with Professor Clive Gray, who provides powerful and valuable insights into the unique research opportunities and immunological advancements supported by Africa's unique blend of social, economic and environmental factors and also discusses the societal and cultural challenges that need to be overcome for equitable research to be achieved across the continent.


Does Movement Contextually Cue Attention During Novel Word Exposure? A Comparison of Preschool Children With Developmental Language Disorder and With Typical Language.
This study investigated the attentional tendencies of preschool children with developmental language disorder (DLD) and their typical language (TL) peers during a word learning task to examine what visual properties of novel objects capture their attention. Twelve children with DLD and 12 children with TL completed a novel name extension task in which they selected which of three visual characteristics of referent objects (i.e., movement, color, pattern) was relevant during novel word-novel referent pairings. No visual feature was more relevant than the others; consequently, there were no correct and no incorrect responses. Children with DLD were systematically different from their TL peers in which visual features of objects they attended to during nonword-novel referent pairings in that they selected movement as the relevant feature of novel objects more often than TL children. There was also a significant negative correlation between chronological age and the propensity for movement selections. In most cases, word learning involves mapping the auditory signal onto visual information. Identifying what children with DLD naturally attend to when exposed to novel word-novel referent pairings is an important first step in order to better understand how to design effective and efficient word learning interventions with this population.


Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N-Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group.
Five platinum(II) complexes bearing a (1,3-dibenzyl)imidazol-2-ylidene ligand but different leaving groups trans to it were examined for cytotoxicity, DNA and cell cycle interference, vascular disrupting properties, and nephrotoxicity. The cytotoxicity of complexes 3a-c increased with the steric shielding of their leaving chloride ligand, and complex 3c, featuring two triphenylphosphanes, was the most efficacious, with submicromolar IC50 concentrations. Complexes 3a-c interacted with DNA in electrophoretic mobility shift and ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, damage that is not amenable to the usual repair mechanisms. Accordingly, it arrested the cell cycle of melanoma cells in G1 phase, whereas cis-dichlorido[(1,3-dibenzyl)imidazol-2-ylidene](dimethyl sulfoxide) platinum(II) 3a induced G2/M phase arrest. Complex 3c also disrupted the blood vessels in the chorioallantoic membrane of fertilized chicken eggs. Ex vivo studies using precision-cut tissue slices suggested the nephrotoxicities of 3a-c to be clinically manageable.


Lifestyle, psychological, socioeconomic and environmental factors and their impact on hypertension during the coronavirus disease 2019 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic considerably affects health, wellbeing, social, economic and other aspects of daily life. The impact of COVID-19 on blood pressure (BP) control and hypertension remains insufficiently explored. We therefore provide a comprehensive review of the potential changes in lifestyle factors and behaviours as well as environmental changes likely to influence BP control and cardiovascular risk during the pandemic. This includes the impact on physical activity, dietary patterns, alcohol consumption and the resulting consequences, for example increases in body weight. Other risk factors for increases in BP and cardiovascular risk such as smoking, emotional/psychologic stress, changes in sleep patterns and diurnal rhythms may also exhibit significant changes in addition to novel factors such as air pollution and environmental noise. We also highlight potential preventive measures to improve BP control because hypertension is the leading preventable risk factor for worldwide health during and beyond the COVID-19 pandemic.


Infrequent p53 mutation in mouse tumors with deregulated myc.
An invariant genetic lesion in mouse plasmacytomas is deregulated expression of c-myc as a consequence of chromosomal translocation. However, retroviral and transgenic studies suggest that additional genetic lesions may contribute to the genesis of plasmacytomas. The p53 tumor suppressor gene is a likely contributor to this genetic lesion, since there is a high incidence of p53 mutation in Burkitt's lymphomas and B-ALL (L3), both of which contain translocations involving c-myc analogous to those in plasmacytomas. In addition, p53 has been shown to be a transcriptional modulator of c-myc expression. In a survey of 27 mouse plasmacytomas by single-strand conformation polymorphism, we identified a single mutation (3.7% incidence), suggesting that p53 lesions are not frequent contributors to plasmacytomagenesis. A similar study of macrophage-monocyte tumors generated by a c-myc-containing retrovirus also indicates a lack of p53 involvement in deregulated c-myc expression. These results suggest that the specific maturation stage of transformed B-lymphocytes, independent of c-myc deregulation, may be the critical factor which determines the involvement of mutant p53.


Broadband supercontinuum generation using a hollow optical fiber filled with copper-ion-modified DNA.
We experimentally demonstrated supercontinuum generation through a hollow core photonic bandgap fiber (HC-PBGF) filled with DNA nanocrystals modified by copper ions in a solution. Both double-crossover nano DNA structure and copper-ion-modified structure provided a sufficiently high optical nonlinearity within a short length of hollow optical fiber. Adding a higher concentration of copper ion into the DNA nanocrystals, the bandwidth of supercontinuum output was monotonically increased. Finally, we achieved the bandwidth expansion of about 1000 nm to be sufficient for broadband multi-spectrum applications.


Premature physeal closure following distal tibia physeal fractures: a new radiographic predictor.
The incidence and predictors of premature physeal closure (PPC) after pediatric distal tibial fractures were investigated. PPC was defined as evidence of growth plate disturbance on the injured side compared with the uninjured side. Ninety-two fractures were reviewed with at least 1 year of follow-up, or until physiologic closure of the growth plates. Twenty-five fractures (27.2%) were complicated by PPC, as confirmed by CT scan in most cases. Salter-Harris III and IV (medial malleolar type) fractures resulted in the highest percentage of PPC by fracture type (38%). Salter-Harris I and II fractures resulted in PPC in 36% of cases, followed by triplane fractures (21%) and Tillaux fractures (0%). Initial displacement, number of reduction attempts, or treatment method did not significantly affect the incidence of PPC. More anatomic reductions resulted in a statistically significant decrease in PPC rates. Residual physeal gap (>3 mm) following reduction was determined from radiographs in Salter-Harris I and II fractures. If a residual gap was seen on the radiograph, the incidence of PPC increased to 60%; if no gap was present, the incidence decreased to 17%. Open reduction was performed in five Salter-Harris II fractures that had a residual gap. Periosteum was entrapped in the physis in all of these cases. Residual gaps in the physis following closed reduction may represent entrapped periosteum in Salter-Harris I and II fractures. This can lead to a higher incidence of PPC, suggesting that open reduction and removal of the entrapped periosteum may be beneficial.


[Synthesis of monoclonal antibodies to tissue-specific antigens of human skin and thymus epithelium in polyclonal activation by pertussis toxin].
Following the immunization of BALB/c mice with B. pertussis toxin, monoclonal antibodies (McAb) to the antigens of human epithelium, both dermal (the basal, superbasal or all epidermis levels) and thymic (the epithelium of the medullary zone, the cortical and medullary epithelium around Hassall's corpuscles), have been obtained. McAb have been obtained as the result of the polyclonal activation of autoreactive B-cells with B. pertussis toxin. McAb thus obtained can be used for the determination of the corresponding antigens in the epithelial tissues of the thymus and other organs in man, as well as for the diagnosis of tumors, histogenetically related to integumentary tissues of the epidermal genesis.


Predicting the 6-month risk of severe hypoglycemia among adults with diabetes: Development and external validation of a prediction model.
To develop and externally validate a prediction model for the 6-month risk of a severe hypoglycemic event among individuals with pharmacologically treated diabetes. The development cohort consisted of 31,674 Kaiser Permanente Colorado members with pharmacologically treated diabetes (2007-2015). The validation cohorts consisted of 38,764 Kaiser Permanente Northwest members and 12,035 HealthPartners members. Variables were chosen that would be available in electronic health records. We developed 16-variable and 6-variable models, using a Cox counting model process that allows for the inclusion of multiple 6-month observation periods per person. Across the three cohorts, there were 850,992 6-month observation periods, and 10,448 periods with at least one severe hypoglycemic event. The six-variable model contained age, diabetes type, HgbA1c, eGFR, history of a hypoglycemic event in the prior year, and insulin use. Both prediction models performed well, with good calibration and c-statistics of 0.84 and 0.81 for the 16-variable and 6-variable models, respectively. In the external validation cohorts, the c-statistics were 0.80-0.84. We developed and validated two prediction models for predicting the 6-month risk of hypoglycemia. The 16-variable model had slightly better performance than the 6-variable model, but in some practice settings, use of the simpler model may be preferred.


Lupus lymphadenitis simulating Kikuchi's lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature.
Kikuchi's disease (KD) or Kikuchi's lymphadenitis (KL) is a self-limiting disease mostly affecting the cervical lymph nodes of young individuals. Whether the reported cases of KL associated with systemic lupus erythematosus (SLE) were genuine KL or lupus lymphadenitis (LL) simulating KL in SLE patients is not clear. We analyzed six cases of KD-like lymphadenitis occurring in SLE patients and 12 reported cases to clarify the relationship between KL and SLE. We found that not all cases occurred simultaneously with SLE. Eight cases occurred either before or after SLE. These cases might have true KL independent of SLE with the exception of two cases that occurred after SLE, but the patients still had lupus activity. The 10 cases that coexisted with SLE most likely had LL rather than KL. This was supported by the immunohistochemical finding of sparse cytotoxic T cells in those lymph nodes in contrast to abundant cytotoxic T cells usually seen in a typical KL. We conclude that KL is not related to SLE, and KD-like lymphadenitis coexisting with SLE should be regarded as LL. Pathologists should be aware of the possibility that LL can mimic KL in patients with SLE, especially necrotizing-type KL.


Bronchial anastomotic complications following lung transplantation: still a major cause of morbidity?
The frequency of bronchial anastomotic complications following lung transplantation has decreased in recent years, but continues to be a potential cause of morbidity and mortality. We have, therefore, reviewed the results of 67 consecutive bronchial anastomoses at risk in 43 patients surviving more than 7 days following lung transplantation. The bronchial anastomoses were performed using a standardized technique, without direct or indirect revascularization. Regular triple immunosuppressive therapy was given, including prednisone (0.5 mg x kg(-1) daily) starting on the day of surgery. Bronchial healing was graded using the Couraud classification. The median follow-up time was 14 months (range 1-45 months). No major airway complications occurred. On 236 serial bronchoscopic examinations, no anastomotic stenoses were observed. One anastomosis showed limited focal necrosis (2 mm) (Couraud 3a), and two anastomoses had partial primary mucosal healing without necrosis (Couraud 2a). In all other anastomoses, primary mucosal healing (Couraud 1) was observed. Carefully performed bronchial anastomosis according to the technique described enables reliable bronchial healing and yields a low complication rate. Additional measures, such as direct revascularization, forced telescoping, omentum wrap and interruption of steroid therapy, are not necessary.


Bringing Emergency Neurology to Ambulances: Mobile Stroke Unit.
Ischemic stroke results from blocked arteries in the brain, with earlier thrombolysis with intravenous tissue plasminogen activator (tPA) and/or mechanical thrombectomy resulting in improved clinical outcomes. Mobile Stroke Unit (MSU) can speed up the treatment with tPA and facilitate faster triage for patients to hospitals for mechanical thrombectomy. The first registry-based MSU study in Germany demonstrated faster treatment times with tPA using a MSU, a higher proportion of patients being treated within the first "golden hour," and a suggestion of improved 3-month clinical outcomes. The first multicenter, prospective, randomized clinical trial comparing MSU versus standard care was started in 2014 after the launch of the MSU in Houston, TX, demonstrating the feasibility and safety of MSU operation in the United States, and reliability of telemedicine to evaluate stroke patients for tPA eligibility. Although conclusive evidence from clinical trials to support MSUs as being cost effective and improving clinical outcomes is still needed, there are a myriad of other clinical and research applications of MSUs that could have profound implications for managing patients with neurological emergencies.


SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration.
Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho -/- sarm1 -/- double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho -/- ) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.


Color Doppler imaging of the ophthalmic artery in patients with chronic heart failure.
To evaluate the ophthalmic artery hemodynamics in patients with chronic heart failure. Doppler parameters of ophthalmic artery of 18 patients with chronic heart failure in different stages of the disease were compared with 21 healthy volunteers (control group). These parameters were also correlated with echocardiographic assessments and clinical cardiologic status. Mean diastolic velocity was 5.14 ± 2.4 cm/s in the chronic heart failure group and 7.44 ± 3.5 cm/s in the control group (p=0.007). Mean resistance index of the ophthalmic artery was 0.76 ± 0.08 in the chronic heart failure group and 0.70 ± 0.08 in the control group (p=0.04). Mean systolic velocity of the ophthalmic artery was 22.03 ± 7.7 cm/s in the chronic heart failure group and 25.32 ± 9.2 cm/s in the control group (p=0.24). There was a negative correlation between the resistance index of the ophthalmic artery and systemic blood pressure of patients with chronic heart failure (r= -0.47, p=0.007). Diastolic velocity of the ophthalmic artery correlated positively with systemic blood pressure (r=0.44, p=0.02). Lower diastolic velocity and higher resistance index were observed in the ophthalmic artery of chronic heart failure patients when compared to the control group, which probably reflects the presence of orbital vasoconstriction in response to low cardiac output. Therefore, the influence of these findings on the structure and function of the optic nerve head deserves investigation.


Cardiovascular Disease Risk-Based Statin Utilization and Associated Outcomes in a Primary Prevention Cohort: Insights From a Large Health Care Network.
Current American College of Cardiology/American Heart Association guidelines recommend using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk to guide statin therapy for primary prevention. Real-world data on adherence and consequences of nonadherence to the guidelines in primary are limited. We investigated the guideline-directed statin intensity (GDSI) and associated outcomes in a large health care system, stratified by ASCVD risk. Statin prescription in patients without coronary artery disease, peripheral vascular disease, or ischemic stroke were evaluated within a large health care network (2013-2017) using electronic medical health records. Patient categories constructed by the 10-year ASCVD risk were borderline (5%-7.4%), intermediate (7.5%-19.9%), or high (≥20%). The GDSI (before time of first event) was defined as none or any intensity for borderline, and at least moderate for intermediate and high-risk groups. Mean (±SD) time to start/change to GDSI from first interaction in health care and incident rates (per 1000 person-years) for each outcome were calculated. Cox regression models were used to calculate hazard ratios for incident ASCVD and mortality across risk categories stratified by statin utilization. Among 282 298 patients (mean age ≈50 years), 29 134 (10.3%), 63 299 (22.4%), and 26 687 (9.5%) were categorized as borderline, intermediate, and high risk, respectively. Among intermediate and high-risk categories, 27 358 (43%) and 8300 (31%) patients did not receive any statin, respectively. Only 17 519 (65.6%) high-risk patients who were prescribed a statin received GDSI. The mean time to GDSI was ≈2 years among the intermediate and high-risk groups. At a median follow-up of 6 years, there was a graded increase in risk of ASCVD events in intermediate risk (hazard ratio=1.15 [1.07-1.24]) and high risk (hazard ratio=1.27 [1.17-1.37]) when comparing no statin use with GDSI therapy. Similarly, mortality risk among intermediate and high-risk groups was higher in no statin use versus GDSI. In a real-world primary prevention cohort, over one-third of statin-eligible patients were not prescribed statin therapy. Among those receiving a statin, mean time to GDSI was ≈2 years. The consequences of nonadherence to guidelines are illustrated by greater incident ASCVD and mortality events. Further research can develop and optimize health care system strategies for primary prevention.


Vascular protection with rivaroxaban in the comprehensive management of atrial fibrillation.
In addition to an increased risk of thromboembolic complications, patients with atrial fibrillation (AF) are at risk for vascular events. Consequently, complete vascular protection is warranted in these patients. A narrative search was conducted on PubMed (MEDLINE), using the MeSH terms [Rivaroxaban] + [Atrial fibrillation] + [Cardiovascular] + [Vascular] + [Treatment]. Original data from clinical trials, prospective and retrospective studies, useful reviews and experimental studies, were selected. The ROCKET-AF trial showed that rivaroxaban is effective in reducing the risk of stroke, with a lower risk of fatal and intracranial bleeding compared to warfarin. Remarkably, experimental data have provided a number of pathogenic mechanisms through which rivaroxaban could provide beneficial vascular properties beyond its antithrombotic activity. Moreover, in the AF population, additional to its ability to reduce the risk of thromboembolic complications, rivaroxaban is associated with a lower risk of myocardial infarction, major adverse cardiac and limb events, and vascular mortality in patients with diabetes, also attenuating renal impairment during follow-up. These findings suggest that rivaroxaban may provide a comprehensive vascular protection in patients with AF.


Biomechanical Assessment of Hip Capsular Repair and Reconstruction Procedures Using a 6 Degrees of Freedom Robotic System.
Although acetabular labral repair has been biomechanically validated to improve stability, capsular management of the hip remains a topic of growing interest and controversy. To biomechanically evaluate the effects of several arthroscopically relevant conditions of the capsule through a robotic, sequential sectioning study. Controlled laboratory study. Ten human cadaveric unilateral hip specimens (mean age, 51.3 years [range, 38-65 years]) from full pelvises were used to test range of motion (ROM) for the intact capsule and for multiple capsular conditions including portal incisions, interportal capsulotomy, interportal capsulotomy repair, T-capsulotomy, T-capsulotomy repair, a large capsular defect, and capsular reconstruction. Hips were biomechanically tested using a 6 degrees of freedom robotic system to assess ROM with applied 5-N·m internal, external, abduction, and adduction rotation torques throughout hip flexion and extension. All capsulotomy procedures (portals, interportal capsulotomy, and T-capsulotomy) created increases in external, internal, adduction, and abduction rotations compared with the intact state throughout the full tested ROM (-10° to 90° of flexion). Reconstruction significantly reduced rotation compared with the large capsular defect state for external rotation at 15° (difference, 1.4°) and 90° (difference, 1.3°) of flexion; internal rotation at -10° (difference, 0.4°), 60° (difference, 0.9°), and 90° (difference, 1.4°) of flexion; abduction rotation at -10° (difference, 0.5°), 15° (difference, 1.1°), 30° (difference, 1.2°), 60° (difference, 0.9°), and 90° (difference, 1.0°) of flexion; and adduction rotation at 0° (difference, 0.7°), 15° (difference, 0.8°), 30° (difference, 0.3°), and 90° (difference, 0.6°) of flexion. Repair of T-capsulotomy resulted in significant reductions in rotation compared with the T-capsulotomy condition for abduction rotation at -10° (difference, 0.3°), 15° (difference, 0.9°), 30° (difference, 1.3°), 60° (difference, 1.7°), and 90° (difference, 1.5°) of flexion and for internal rotation at -10° (difference, 0.9°), 60° (difference, 1.5°), and 90° (difference, 2.6°) of flexion. Similarly, repair of interportal capsulotomy resulted in significant reductions in abduction (difference, 0.9°) and internal (difference, 1.4°) rotations compared with interportal capsulotomy at 90° of flexion. In most cases, however, after the repair procedures, ROM was still increased in comparison with the intact state. The results of this study suggest that common hip arthroscopic capsulotomy procedures can result in increases in external, internal, abduction, and adduction rotations throughout a full range (-10° to 90°) of hip flexion. However, capsular repair and reconstruction succeeded in partially reducing the increased rotational ROM caused by common capsulotomy procedures. Thus, consideration should be allotted toward capsular repair or reconstruction in cases with an increased risk of residual instability. Although complete restoration of joint stability may not be fully achieved at time zero, capsular repair and reconstruction may lead to improved patient outcomes by bringing hip rotational movements nearer to normal values in the immediate postoperative period, especially in cases in which extensive capsulotomy is performed.


Effect of N6-(L-2-phenylisopropyl)adenosine and insulin on cAMP metabolism in 3T3-L1 adipocytes.
The antilipolytic effect of N6-(L-2-phenylisopropyl)-adenosine (PIA), an adenosine analogue thought to act via cell surface receptors, was investigated in 3T3-L1 adipocytes. PIA (1 microM) was as effective as 1 nM insulin in reducing lipolysis stimulated by 1 nM isoproterenol and more effective than insulin at higher isoproterenol concentrations. In intact adipocytes, PIA reduced isoproterenol-induced cyclic AMP (cAMP) accumulation and increased particulate cAMP phosphodiesterase. In particulate preparations PIA suppressed isoproterenol stimulation of adenylate cyclase. PIA was more effective than 5'-N-ethylcarboxamide adenosine (NECA) or adenosine in inhibiting adenylate cyclase and activating phosphodiesterase. In intact adipocytes, two agents with so-called "insulin-like" activities, i.e., anti-insulin receptor antibodies and wheat germ agglutinin (WGA), also increased particulate cAMP phosphodiesterase. Pertussis toxin, which inhibits stimulation of the particulate cAMP phosphodiesterase by insulin (but not by isoproterenol), also inhibited the effects of PIA, anti-insulin receptor antibodies, and WGA. In 3T3-L1 cells, PIA appears to inhibit lipolysis by inhibiting adenylate cyclase and stimulating phosphodiesterase; these effects of PIA, as well as those of anti-insulin receptor antibodies and WGA on phosphodiesterase, may be mediated via guanyl nucleotide-binding proteins.


Tissue-specific expression of the rat pancreatic elastase I gene in transgenic mice.
The gene for rat pancreatic elastase I is selectively expressed to high levels in the rat exocrine pancreas. When the cloned rat elastase I gene with 7 kb upstream and 5 kb downstream flanking sequences was introduced into mice by microinjection into fertilized eggs, the gene was expressed in a pancreas-specific manner. In four of five transgenic mice, the level of rat elastase I mRNA in the pancreas was equal to or greater than the normal rat level (10,000 mRNAs per cell) and correlated with the number of integrated gene copies. In nonpancreatic tissues the levels were at least 10(3)-fold lower, except for expression in the liver of one mouse. Thus transfer of a 23 kb genomic DNA segment containing the rat elastase I gene to a foreign chromosomal location in the mouse can give rise to qualitatively and quantitatively normal expression.


Solving audiometric masking dilemmas with an insert masker.
For some bilateral hearing losses, standard audiometric techniques cannot provide sufficient data for correct otologic diagnosis. These hearing losses are termed "masking dilemmas" because sound attenuation across the head is inadequate to prevent unwanted masking of the test cochlea. In most cases, the masking dilemma can be eliminated by presenting masking through an insert phone in the ear canal, rather than through a standard earphone and cushion. Insert earphones are not standard on most audiometers, but the minimal necessary equipment and alterations are inexpensive, readily available, and require little time to implement. Test time is not increased significantly. Some masking dilemmas will not be solved by the insert masker, but, when properly constructed and used, an insert masker will provide an accurate measurement of cochlear reserve not otherwise obtainable for most cases.


The effect of repeated measurements and working memory on the most comfortable level in the ANL test.
To study the effect of a large number of repetitions on the most comfortable level (MCL) when doing the acceptable noise level (ANL) test, and explore if MCL variability is related to central cognitive processes. Twelve MCL repetitions were measured within the ANL test using interleaved methodology during one session using a non-semantic version. Phonological (PWM) and visuospatial working memory (VSWM) was measured. Thirty-two normal-hearing adults. Repeated measures ANOVA, intraclass correlations, and the coefficient of repeatability (CR) were used to assess the repeatability. Repeated measures ANOVA and CR indicated poor agreement between the two first repetitions. After excluding the first repetition, analyses showed that the MCL in the ANL test is reliable. A negative association was found between PWM and MCL variability indicating that subjects with higher PWM show less variability. The findings suggest that, after excluding the first repetition, the MCL in the ANL test is reliable. A single repetition of the MCL in the ANL test should be avoided. If an interleaved methodology is used, a single ANL repetition should be added prior to the actual testing. The findings also suggest that MCL variability is associated to PWM but not VSWM.


Phytohormones as Regulators of Mitochondrial Gene Expression in Arabidopsis thaliana.
The coordination of activities between nuclei and organelles in plant cells involves information exchange, in which phytohormones may play essential roles. Therefore, the dissection of the mechanisms of hormone-related integration between phytohormones and mitochondria is an important and challenging task. Here, we found that inputs from multiple hormones may cause changes in the transcript accumulation of mitochondrial-encoded genes and nuclear genes encoding mitochondrial (mt) proteins. In particular, treatments with exogenous hormones induced changes in the GUS expression in the reporter line possessing a 5'-deletion fragment of the RPOTmp promoter. These changes corresponded in part to the up- or downregulation of RPOTmp in wild-type plants, which affects the transcription of mt-encoded genes, implying that the promoter fragment of the RPOTmp gene is functionally involved in the responses to IAA (indole-3-acetic acid), ACC (1-aminocyclopropane-1-carboxylic acid), and ABA (abscisic acid). Hormone-dependent modulations in the expression of mt-encoded genes can also be mediated through mitochondrial transcription termination factors 15, 17, and 18 of the mTERF family and genes for tetratricopeptide repeat proteins that are coexpressed with mTERF genes, in addition to SWIB5 encoding a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein. These genes specifically respond to hormone treatment, displaying both negative and positive regulation in a context-dependent manner. According to bioinformatic resources, their promoter region possesses putative cis-acting elements involved in responses to phytohormones. Alternatively, the hormone-related transcriptional activity of these genes may be modulated indirectly, which is especially relevant for brassinosteroids (BS). In general, the results of this study indicate that hormones are essential mediators that are able to cause alterations in the transcript accumulation of mt-related nuclear genes, which, in turn, trigger the expression of mt genes.


Coronary heart disease incidence among non-Western immigrants compared to Danish-born people: effect of country of birth, migrant status, and income.
Increasing global migration has made immigrants' health an important topic worldwide. We examined the effect of country of birth, migrant status (refugee/family-reunified) and income on coronary heart disease (CHD) incidence. This was a historical prospective register-based cohort study. The study cohort consisted of immigrants above 18 years from non-Western countries who had obtained a residence permit in Denmark as a refugee (n = 29,045) or as a family-reunified immigrant (n = 28,435) from 1 January 1993-31 December 1999 and a Danish-born reference population (n = 229,918). First-time CHD incidence was identified from 1 January 1993-31 December 2007. Incidence ratios for 11 immigrant groups were estimated using Cox regression analysis. Immigrants from Afghanistan, Iraq, Turkey, Eastern Europe and Central Asia, South Asia, the Former Yugoslavia, and the Middle East and North Africa had significantly higher incidences of CHD (hazard ratio (HR) = 1.36; 95% confidence interval (CI): 1.05-1.75 to HR = 2.86; 95% CI: 2.01-4.08) compared with Danish-born people. Immigrants from Somalia, South and Middle America, Sub-Saharan Africa and women from East Asia and the Pacific did not differ significantly from Danish-born people, whereas immigrant men from East Asia and the Pacific had a significantly lower incidence (HR = 0.32; 95% CI: 0.17-0.62). When also including migrant status, the higher incidences were reduced. Refugee men (HR = 1.35; 95% CI: 1.11-1.65) and women (HR = 1.33; 95% CI: 1.08-1.65) had a significantly higher incidence of CHD than family-reunified immigrants. When migrant status and income were included simultaneously, the incidences decreased to an insignificant level for most immigrant groups. Most non-Western immigrant groups had a higher incidence of CHD than Danish-born people. The study revealed that migrant status and income are important underlying mechanisms of the effect of country of birth on CHD.


The role of metabolomics in tuberculosis treatment research.
Despite the fact that tuberculosis (TB) is a curable disease, it still results in approximately 1.8 million deaths annually. Various inadequacies in the current TB treatment strategies are major contributors to this high disease prevalence, including the long duration of therapy, the severe side effects associated with TB drugs, treatment failure due to drug resistance, post-treatment disease relapse, and HIV co-infection. In this review, we describe how metabolomics has contributed toward better explaining/elucidating the mechanisms of drug action/metabolism, drug toxicity and microbial drug resistance, and how metabolite biomarkers may serve as prognostic indicators for predicting treatment outcome as well as for the development of new TB drugs. We also discuss possible future contributions that metabolomics can make toward more efficient, less toxic TB treatment strategies.


Controversies in hydrating the terminally ill patient.
It is a common practice in healthcare to provide comfort and relief from distressing symptoms with the use of intravenous fluids when the patient is no longer able to ingest an adequate amount of fluid. If hydration is not provided to a patient, the medical professional is thought to be negligent of the patient's needs, to consign the patient to a horrible death, and even to shorten the patient's life. On the contrary, dehydration in terminal illness has not been found to produce distressing symptoms or to shorten life span; it may even be beneficial.


Whole-genome resequencing of wild and domestic sheep identifies genes associated with morphological and agronomic traits.
Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.


Co-Sleeping between Adolescents and Their Pets May Not Impact Sleep Quality.
Pet-owner co-sleeping is increasingly common in some parts of the world. Adult owners often subjectively report benefits of co-sleeping with pets, although objective actigraphy reports conversely indicate sleep disruptions due to the pet. Because limited research is available regarding pet-owner co-sleeping in non-adult samples, the aim of this two-part study was to explore whether co-sleeping improves sleep quality in adolescents, an age group in which poor sleep patterns are well documented. In Study One, an online survey with 265 pet-owning 13-to-17-year-old participants found that over 78% co-slept with their pet. Average sleep quality scores for co-sleepers and non-co-sleepers indicated generally poor sleep, with no differences in sleep quality depending on age, gender, or co-sleeping status. Study Two consisted of two preliminary case studies, using actigraphy on dog-adolescent co-sleepers. In both cases, high sleep concordance was observed, but owners again experienced generally poor sleep quality. Future actigraphy research is needed, including larger sample sizes and a control group of non-co-sleepers, to validate the preliminary findings from this study, but our limited evidence suggests that co-sleeping with a pet may not impact sleep quality in adolescents.


Cross-Cultural Adaptation Of The Persian Version Of Test Of The Adherence To Inhalers (TAI).
Despite the importance of using inhalers concerning chronic obstructive pulmonary disease (COPD), patients generally have problems regarding adherence to medication regimen. The first step in understanding medication adherence is its assessment which requires a reliable tool. The aim of this study was to translate and perform the psychometric assessment of Test of Adherence to Inhalers (TAI). In this cross-sectional study, the 10-item TAI was utilized. Patients with COPD referring to Amir-al-Momenin and Vali-Asr hospitals in Arak, Iran, were the study population. The tool was translated using forward-backward translation, and its validity was evaluated via face validity, content validity, and concurrent validity. The reliability of the tool was assessed using test-retest and Cronbach's alpha. A total of 100 patients with COPD participated in the study, where the results showed that the tool has a good face validity. The CVR was 0.83, the CVI was 0.95, and the concurrent validity with General Medication Adherence Scale (GMAS) was moderate which was not significant (r = 0.613, p = 0.06). The results of the reliability test further showed that in the test-retest, Pearson correlation coefficient was 0.986, ICC was 0.972, and Cronbach's alpha was 0.986. The tool was translated to Farsi language, with the results indicating that Farsi TAI is a valid and reliable tool for measuring inhaler adherence in patients with chronic pulmonary disease.


Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.


Skull shape evolution in durophagous carnivorans.
In this article, we investigate convergent evolution toward durophagy in carnivoran skull shape using geometric morphometrics in a sample of living and extinct species. Principal components analysis indicate that, in spite of the different dietary resources consumed by durophages-that is, bone-crackers and bamboo-feeders-both groups of carnivorans share portions of skull phenotypic spaces. We identify by discriminant analyses a shared set of adaptations toward durophagy in the skull of carnivores. However, ancestral states indicate that although durophages reached similar phenotypes, the evolutionary pathways that they followed are different depending upon the family to which they belong. Furthermore, while the carnivoran cranium more closely reflects the nature of the resources consumed-that is, soft or hard and tough items-the mandible shows particular feeding adaptations-that is, bamboo or bone. This finding supports the interpretation that the mandible has more evolutionary plasticity than the cranium, which is more limited to evolve toward a particular feeding adaptation. However, we find that the shapes of the cranium and the mandible are highly integrated for the whole order Carnivora. Published studies of teratological cats and dogs indicate that the role of internal constraints in shaping this pattern of integration is absent or weak and malleable by selection.


PathCase: pathways database system.
As the blueprints of cellular actions, biological pathways characterize the roles of genomic entities in various cellular mechanisms, and as such, their availability, manipulation and queriability over the web is important to facilitate ongoing biological research. In this article, we present the new features of PathCase, a system to store, query, visualize and analyze metabolic pathways at different levels of genetic, molecular, biochemical and organismal detail. The new features include: (i) a web-based system with a new architecture, containing a server-side and a client-side, and promoting scalability, and flexible and easy adaptation of different pathway databases, (ii) an interactive client-side visualization tool for metabolic pathways, with powerful visualization capabilities, and with integrated gene and organism viewers, (iii) two distinct querying capabilities: an advanced querying interface for computer savvy users, and built-in queries for ease of use, that can be issued directly from pathway visualizations and (iv) a pathway functionality analysis tool. PathCase is now available for three different datasets, namely, KEGG pathways data, sample pathways from the literature and BioCyc pathways for humans. Available online at http://nashua.case.edu/pathways


The proppin Bcas3 and its interactor KinkyA localize to the early phagophore and regulate autophagy.
To resolve the signaling mechanisms that mediate the starvation-induced processes of Dictyostelium sporulation and encystation, we performed insertional mutagenesis on cells harboring an mRFP-tagged spore gene. We isolated a mutant in kinkyA (knkA), a gene without known function, which formed fruiting bodies with a kinked stalk and lacking viable spores. Immunoprecipitation of lysates of KnkA-YFP-transformed knkA- cells yielded a mammalian BCAS3 homolog as a KnkA interactor. bcas3- phenocopied knkA- and Bcas3 colocalized with KnkA to puncta. Bcas3 shares sequence similarity with proppins (beta-propellors that bind phosphoinositides). Mutation of 2 Bcas3 residues that are essential for PtdIns3P binding in proppins prevented Bcas3 binding to PtdIns3P as well as punctate Bcas3 and KnkA localization. KnkA puncta also colocalized with small but not large vesicles that contain the autophagy protein Atg8 and were contiguous with the endoplasmic reticulum. knkA- and bcas3- cells showed a pronounced decrease of RFP-GFP-Atg8 in neutral early autophagosomes, indicating that KnkA and Bcas3 are required for macroautophagy/autophagy. Knockouts in atg7, atg5 or atg9 substantiated this finding by showing similar sporulation defects as knkA- and bcas3-. Defective Dictyostelium sporulation is evidently a useful diagnostic tool for the discovery of novel autophagy genes.Abbreviations: Atg: Autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; cAMP: 3',5'-cyclic adenosine monophosphate; ER: endoplasmic reticulum; GFP: green fluorescent protein; PAS: phagophore assembly site; PRKA/PKA: protein kinase cAMP-dependent; Proppin: beta-propellers that bind phosphoinositides; PtdIns3P: phosphatidylinositol 3-phosphate; REMI: restriction enzyme-mediated insertional mutagenesis; RFP: red fluorescent protein; RT-qPCR: reverse transcriptase - quantitative polymerase chain reaction; WIPI: WD repeat domain, phosphoinositide interacting; YFP: yellow fluorescent protein.


Common genes in coronary artery disease from Europe, Asia and North America regardless of race and lifestyle.
Coronary artery disease (CAD) remains one of the major causes of death worldwide. Despite considerable advances in the prevention and treatment of CAD, its complications, morbidity and mortality still remain very high, and vary widely across different ethnic groups. To detect genes involved in the development of CAD, we collected gene expression studies in the blood samples of CAD patients from different continents by searching the Gene Expression Omnibus database (GEO), performed a comparative analysis of gene expression between CAD patients and normal controls (NC) in each continent and identified the common set of differentially expressed genes (DEGs) between CAD patients and NC across different continents. PPI networks of the common set of DEGs were established by Cytoscape software to understand their biological role in CAD. A total of 575, 868 and 476 genes were identified to be significantly differentially expressed between CAD patients and NC in Asia, Europe and North America. 24 genes were found common in three different continents, and 6 genes were previously linked to CAD or atherosclerosis. In the PPIs network the significant hub proteins contained IRF4 (Degree = 23), PLAUR (Degree = 17) and HIST1H2AE (Degree = 15). Not only did we detect gene expression differences in the blood samples between CAD and NC in Asia, Europe and North America population, but analysis of the three population groups revealed a common set of 24 genes regardless of differences related to race, ethnicity, lifestyle, and environmental factor which may provide key factors to understand the pathogenesis of CAD and lead to development of diagnostic markers and/or effective therapeutic strategies.


Zonal distribution of alveolar macrophages, type II pneumonocytes, and alveolar septal connective tissue gaps in adult human lungs.
The distribution of alveolar macrophages, Type II cells, and alveolar septal connective tissue discontinuities or gaps in two neighboring alveoli from a human lung obtained at surgery, and preserved by vascular perfusion-fixation, was studied by electron microscopy. Discontinuities or gaps are defined as complete interruptions of all the connective tissue elements of the alveolar septum, including the basement membranes. Serial-sectioning of the alveoli, and the creation of montages of the entire circumference of each alveolus at intervals of every twentieth section (approximately 1.6 micron) at a magnification of X 2,160 permitted precise identification of cells and connective tissue gaps and allowed the reconstruction, by computer techniques, of the alveolar walls in 3 dimensions. These studies showed that all of the 48 alveolar macrophages identified, and over two thirds of all Type II cells and alveolar septal gaps, were located or bordered on alveolar septal junctional zones (within 10 microns of septal junctions). The profiles of 739 alveoli examined by light microscopy from 6 lungs similarly preserved by vascular perfusion-fixation, in which the alveolar surface lining was well fixed, also showed alveolar macrophages preferentially distributed in alveolar junctional zones. These were compared with 242 alveolar profiles from 3 other vascularly-fixed lungs and 971 alveolar profiles from 9 lungs fixed by way of the airways, in which the alveolar surface lining was lost. In these lungs, most of the alveolar macrophages were in the alveolar air spaces.(ABSTRACT TRUNCATED AT 250 WORDS)


Clock-Enhancing Small Molecules and Potential Applications in Chronic Diseases and Aging.
Normal physiological functions require a robust biological timer called the circadian clock. When clocks are dysregulated, misaligned, or dampened, pathological consequences ensue, leading to chronic diseases and accelerated aging. An emerging research area is the development of clock-targeting compounds that may serve as drug candidates to correct dysregulated rhythms and hence mitigate disease symptoms and age-related decline. In this review, we first present a concise view of the circadian oscillator, physiological networks, and regulatory mechanisms of circadian amplitude. Given a close association of circadian amplitude dampening and disease progression, clock-enhancing small molecules (CEMs) are of particular interest as candidate chronotherapeutics. A recent proof-of-principle study illustrated that the natural polymethoxylated flavonoid nobiletin directly targets the circadian oscillator and elicits robust metabolic improvements in mice. We describe mood disorders and aging as potential therapeutic targets of CEMs. Future studies of CEMs will shed important insight into the regulation and disease relevance of circadian clocks.


Racial and ethnic differences in pediatric obesity-prevention counseling: national prevalence of clinician practices.
To assess the frequency of clinician-reported delivery of obesity-prevention counseling (OPC) at well-child visits; evaluating for racial/ethnic discrepancies. Combined, weighted well-child visit data from the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2001 to 2004 were analyzed for patients aged 4-18 years. Obesity-prevention counseling was defined as the combined delivery of diet/nutrition and exercise counseling. Patients receiving over- or underweight related diagnoses were excluded. Counseling frequencies were calculated. Multivariate logistic regression models examined the relationship of OPC with race, ethnicity, region, provider, sex, age, and payor type. Of 55,695,554 (weighted) visits, 24.4% included OPC (90.8% of these from NAMCS). 15.4% of Hispanic patients received OPC compared to 28.8% of non-Hispanics. Frequencies were similar between Whites and Blacks (25.0 and 27.1%). Patients with private insurance received more counseling (26.9%) than Medicaid (19.1%) or self-pay (15.1%). In logistic regression models, non-Hispanics were more likely to receive OPC (odds ratio (OR) = 1.94; confidence interval (CI) = 1.13-3.32), and patients in the West were less likely to receive OPC (OR = 0.39; CI = 0.18-0.85). Payor type was not predictive in regression analysis. Patients in hospital-based practices received less OPC (11.9% vs. 25.7% with OR = 0.40; CI =0.22-0.74). Obesity prevention, like treatment, is a complex and multifactorial process. With the documented racial and ethnic disparities in rates of pediatric obesity, reasons for discrepancies in the provision of OPC must be further investigated as preventive strategies are formulated.


Nucleic acid binding and other biomedical properties of artificial oligolysines.
In the present study, we report the interaction of an artificial oligolysine (referred to as AOL) realized in our laboratory with targets of biomedical importance. These included polyinosinic acid (poly rI) and its complex with polycytidylic acid (poly I:C), RNAs with well-known interferon-inducing ability, and double-stranded (ds) DNA. The ability of the peptide to bind both single-stranded poly rI and ds poly I:C RNAs emerged from our circular dichroism (CD) and ultraviolet (UV) studies. In addition, we found that AOL forms complexes with dsDNA, as shown by spectroscopic binding assays and UV thermal denaturation experiments. These findings are encouraging for the possible use of AOL in biomedicine for nucleic acid targeting and oligonucleotide condensation, with the latter being a key step preceding their clinical application. Moreover, we tested the ability of AOL to bind to proteins, using serum albumin as a model protein. We demonstrated the oligolysine-protein binding by CD experiments which suggested that AOL, positively charged under physiological conditions, binds to the protein regions rich in anionic residues. Finally, the morphology characterization of the solid oligolysine, performed by scanning electron microscopy, showed different crystal forms including cubic-shaped crystals confirming the high purity of AOL.


Molecular characterization of extended-spectrum β-lactamase, plasmid-mediated AmpC cephalosporinase and carbapenemase genes among Enterobacteriaceae isolates in five medical centres of East and West Azerbaijan, Iran.
Very little is known about the occurrence and various types of extended-spectrum β-lactamase (ESBL), AmpC and carbapenemase in Iran. The aims of this study were to determine the prevalence of ESBLs, AmpCs and carbapenemase genes among Enterobacteriaceae in Azerbaijan and to characterize the genetic composition of the detected genes. A total of 307 Enterobacteriaceae isolates, recovered from five medical centres, were screened for ESBL, AmpC and carbapenemase activities by the disc diffusion method and phenotypic confirmatory tests. The 162 selected strains (third-generation cephalosporins, cefoxitin- or carbapenem-resistant strains with positive or negative phenotypic confirmatory tests) were selected for multiplex PCR screening for β-lactamase genes, and detected genes were confirmed by sequencing. Of 162 isolates, 156 harboured 1 to 6 β-lactamase genes of 41 types. The most prevalent genes were blaTEM-1 (29.9 %), followed by blaCTX-M-15 (25.7 %). Plasmid-mediated AmpC was detected in 66 strains (21.5 %) alone or in combination with other genes. Carbapenemase-encoding genes were detected in 18 strains (5.8 %) of 27 carbapenem-non-susceptible isolates including 11, 7, 3 and 1 cases of blaOXA-48, blaNDM-1, blaKPC-2 and blaKPC-3 genes, respectively. Interestingly, 148 (94.8 %) of 156 strains with any β-lactamase gene were found to have a multidrug-resistant pattern. The rate of resistance to β-lactams and multidrug-resistant Enterobacteriaceae is high in Azerbaijan. All positive strains for carbapenemase genes were resistant to all β-lactams. The present study reveals the high occurrence of CTX-M-type ESBLs followed by TEM and SHV variants among Enterobacteriaceae isolates. East Azerbaijan seems to be an alarming focus for OXA-48, NDM-1 and KPC dissemination.


De novo donor-specific human leukocyte antigen antibodies early after kidney transplantation.
Our aim was to determine the incidence of de novo donor-specific human leukocyte antigen (HLA) antibody (dnDSA) during the first year after kidney transplantation and the impact of early dnDSA on acute rejection and protocol biopsy findings. We selected all patients who received a kidney transplant at our center between July 2010 and March 2012. Single antigen bead assay was performed at 1, 4 and 12 months after transplantation. Only DSAs with a mean fluorescence intensity (MFI) of greater 999 were included. We included 245 kidney transplant recipients who did not have a DSA before transplantation. At 12 months, 8.2% of the patients developed dnDSA; 2.4% of them were to HLA class I and 6.5% to HLA class II. Of the 32 patients with a dnDSA at 1 or 4 months, only 8 (25%) persisted at 12 months. The risk of antibody-mediated rejection (AMR) was higher in the dnDSA group. For the dnDSA group with MFI of 3,000 or greater (compared with the group with MFI<3,000), the hazard ratio for AMR was 10.6 (95% confidence interval, 2.27-49.5). The cumulative incidence of AMR or mixed rejection at 1 year was 30% in the group with dnDSA MFI level of 3,000 or greater but only 4% for the group with dnDSA with MFI less than 3,000. On 1-year protocol biopsies, the dnDSA group showed more interstitial inflammation, tubulitis, and glomerulitis. We conclude that dnDSA occurring during the first posttransplantation year may be transient, and the risk of AMR is higher in patients with a dnDSA MFI level that is greater than 3,000.


Biomechanics of single-leg running using lofstrand crutches in amputee soccer.
[Purpose] Amputee soccer is a game for individuals with amputations. Players use lofstrand crutches to move around the field and kick the ball. Scoring quick goals during a match requires players to have maximum running skills. Notably, a few parameters affect the running speed in players; however, no study has reported the biomechanical analysis of running in amputee soccer. Thus study aimed to analyze the biomechanics of single-leg running using lofstrand crutches in 12 healthy adult males (6 with prior amputee soccer experience and 6 without such experience). [Participants and Methods] The kinematics of the lower limb and the pelvis, the ground reaction force, and skill in using the crutches were evaluated using 3 dimensional motion analysis combined with 8 force plates. Lower leg amputation was simulated in all participants by maintaining the non-dominant knee in a position of maximum flexion using an elastic band. [Results] Significant differences were observed between experienced and non-experienced participants with regard to the angle of the pelvis and the crutch stance phase. Specifically, higher running speed was associated with an increased forward tilt of the pelvis and a shorter crutch stance phase. [Conclusion] These findings will be useful to improve the running speed of amputee soccer players.


High food abundance permits the evolution of placentotrophy: evidence from a placental lizard, Pseudemoia entrecasteauxii.
Mechanisms of reproductive allocation are major determinants of fitness because embryos cannot complete development without receiving sufficient nutrition from their parents. The nourishment of offspring via placentas (placentotrophy) has evolved repeatedly in vertebrates, including multiple times in squamate reptiles (lizards and snakes). Placentotrophy has been suggested to evolve only if food is sufficiently abundant throughout gestation to allow successful embryogenesis. If scarcity of food prevents successful embryogenesis, females should recoup nutrients allocated to embryos via abortion, reabsorption, and/or cannibalism. We tested these hypotheses in the placentotrophic southern grass skink Pseudemoia entrecasteauxii. We fed females one of four diets (high constant, high variable, low constant, and low variable) during gestation and tested the effects of both food amount and schedule of feeding on developmental success, cannibalism rate, placental nutrient transport, offspring size, and maternal growth and body condition. Low food availability reduced developmental success, placental nutrient transport, offspring size, and maternal growth and body condition. Cannibalism of offspring also increased when food was scarce. Schedule of feeding did not affect offspring or mothers. We suggest that high food abundance and ability to abort and cannibalize poor-quality offspring are permissive factors necessary for placentotrophy to be a viable strategy of reproductive allocation.


Prevalence of dental anomalies in patients with cleft lip and palate, Paraiba, Brazil: clinic and radiographic study.
The aim of this study is to investigate the prevalence of dental anomalies in a group of individuals with different types of clefts attending the reference service in orthodontics for the care of patients with clefts in Paraiba state, northeastern Brazil. This was a cross-sectional, observational study. Two previously trained examiners (kappa = 0.89) performed the clinical examination of 76 patients with post and incisive transforamen unilateral or bilateral clefts, of both sexes, aged 4 to 32 years, and the analysis of periapical and panoramic radiographs from archived records of these patients. Only the upper front teeth were evaluated. Data were processed by descriptive statistics and subjected to statistical Chi-square test considered significant at 5%. Among the patients evaluated, males (57.9%) and left unilateral transforamen clefts (40.8%) were prevalent. Of the total 76 patients examined, 56 (73.68%) had at least one dental anomaly, the most frequent being agenesis (31.6%) and conical teeth (28.9%). The presence of anomalies differed significantly between the cleft and the contralateral sides (p<0.00001). The diagnosis and treatment of patients with clefts should therefore receive more attention. It is suggested that clinical and radiographic examination be performed together with careful planning and implementation of specialist services in an effort to provide early and adequate detection and treatment.


Glut-1 Expression Correlates with Basal-like Breast Cancer.
Glucose transporter 1 (Glut-1) is a facilitative glucose transporter expressed in many cancers including breast cancer. Basal-like breast cancer (BLBC) is a high-risk disease associated with poor prognosis and lacks the benefit of targeted therapy. The aim of this study was to characterize the immunohistochemical (IHC) expression of Glut-1 in patients with BLBC compared with non-BLBC. We identified 523 cases of invasive breast carcinoma from our database. The clinicopathologic findings and the biologic markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) status were reviewed. IHC stains for cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), p53, and Glut-1 were performed on tissue microarray using standard procedures. BLBC was defined as ER-,PR-, Her2-, and CK5/6+ and/or EGFR+. Of informative cases, 14.7% were categorized as BLBC versus 85.3% as non-BLBC. Glut-1 was expressed in 42 (76.4%) of 55 BLBCs, whereas only 55 (23.8%) of 231 non-BLBCs showed immunostaining for Glut-1 (P < .001). Overall, Glut-1 expression was significantly associated with high histologic grade, ER negativity, PR negativity, CK5/6 positivity, EGFR expression, and high p53 expression (P < .001). However, there was no correlation between Glut-1 immunostaining and patient's outcome. Our results show that Glut-1 is significantly associated with BLBC and might be a potential therapeutic target for this aggressive subgroup of breast cancer, and this warrants further investigations.


Lessons learnt from a nationally funded training and mentoring programme for early-mid career musculoskeletal researchers in Australia.
Quality training and mentoring are crucial components of successful career development for early mid career researchers (EMCRs). This paper describes the overarching framework of novel ongoing national Training and Mentoring Programme Melbourne University Sydney Queensland:Impact (MUSQ:Impact) for musculoskeletal researchers, including a description of how it was set up and established, and lessons learned from its implementation. The MUSQ:Impact programme spans four multidisciplinary musculoskeletal research teams across three universities in Australia, comprising 40-60 EMCR members. It was established to provide EMCRs with a unique learning environment and opportunities to gain exposure to, and network with, other national musculoskeletal research teams. Specific goals are to focus on core research competencies (e.g. writing skills, managing grant budgets, public speaking and media engagement, research translation), provide career mentoring, fund development activities (e.g. conference attendance, laboratory visits, skill development courses), and share training resources (e.g. data dictionaries, project summaries). A Steering Committee of 10-12 EMCR members, co-chaired by a senior researcher and one EMCR, is responsible for overseeing MUSQ:Impact and organising regular activities, including a monthly webinar series, a mentor/mentee scheme, annual group research retreats, annual infographic competition, and funding awards. An evaluation survey found that most participants perceived each activity to be beneficial and of value to their research career and development. This paper presents the structure of national training and mentoring programme that serves as a potential template for other research teams to adapt within their own contexts.