Expressions of Matrix Metalloproteinases-9 and Tissue Inhibitor of Metalloproteinase-1 in Pituitary Adenomas and Their Relationships with Prognosis.
To investigate the expression levels of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in pituitary adenomas (PAs), and to analyze the relationship of the expressions of the two with the prognosis of patients. A total of 108 patients with PAs diagnosed in our hospital from May 2010 to May 2012 were selected and divided into the invasive PA (IPA) group (n = 58) and the non-IPA group (n = 50) according to the invasiveness of PAs. Hematoxylin and eosin (H&E) staining was used to observe the pathological state of patients. The expression levels of MMP-9 and TIMP-1 were measured by immunohistochemistry and western blotting at protein level and reverse transcription-polymerase chain reaction at gene level, respectively. The expression levels of MMP-9 and TIMP-1 in serum of patients before operation were tested using enzyme-linked immunosorbent assay, and patients with PAs after operation were followed up. The positive expression rate of MMP-9 in IPAs was significantly higher than that in non-IPAs, whereas that of TIMP-1 was relatively high in non-IPAs, and the differences were statistically significant (p < 0.05). At both protein and gene levels, MMP-9 was highly expressed in IPAs, whereas TIMP-1 was highly expressed in non-IPAs, and the differences were statistically significant (p < 0.05 in all comparisons). Before operation, the expression level of MMP-9 in serum of patients with IPAs was relatively high, whereas that of TIMP-1 in serum of patients with non-IPAs was relatively high, and the differences were statistically significant (p < 0.05 in all comparisons). The postoperative survival rate of patients with highly expressed MMP-9 was relatively low, whereas that of patients with highly expressed TIMP-1 was relatively high. The abnormal expressions of MMP-9 and TIMP-1 play important roles in the invasion process of PAs. The prognoses of patients with low expression MMP-9 and high expression TIMP-1 are more positive.


The influence of patent foramen ovale on oxygen desaturation in obstructive sleep apnoea.
Obstructive sleep apnoea (OSA) is associated with oxygen desaturation to a varying degree. A patent foramen ovale (PFO) may allow interatrial right-to-left shunting. The hypothesis of the current study was that oxygen desaturation will occur more often, in proportion to the frequency of respiratory disturbances, in OSA subjects with PFO than in those without. In a group of 209 subjects diagnosed with OSA, the proportion of desaturation to respiratory events was calculated as the ratio of oxygen desaturation index (ODI)/apnoea-hypopnoea index (AHI). A total of 15 cases with high proportional desaturation (ODI/AHI >or=0.66) were individually matched with 15 controls with low proportional desaturation (ODI/AHI <or=0.33), all without pulmonary disease. PFO was assessed with contrast transoesophageal echocardiography and considered large when >or=20 bubbles passed over from the right to the left atrium after a single injection. The prevalence of large PFO was nine out of 15 (60%) in the high proportional desaturation group versus two out of 15 (13%) in the low proportional desaturation group. The median number of passing bubbles was positively correlated to minimum oxygen saturation among those with PFO. In conclusion, oxygen desaturation occurs more often, in proportion to the frequency of respiratory disturbances, in obstructive sleep apnoea subjects with a patent foramen ovale than in those without.


[Diabetic neuropathy. II. Autonomic neuropathy. The gastrointestinal system].
Autonomic diabetic neuropathy of the alimentary canal takes several basic forms: a) oesophagopathy , b) gastroparesis, c) enteropathy, d) bile duct disorders. In many cases three are no subjective symptoms. In other the onset of the clinical condition may take acute and dangerous forms as in gastropathy. In still other cases e.g. enteropathy, the neuropathy may develop in bizarre and unexpected ways which are highly damaging to the patient's quality of life though in most cases they are not fatal. Bile disorders involving minimal motility after stimulus, as in denervation and reduced sensitivity to pain are particularly significant. Diabetics are more likely to suffer from calculosis (59.6% of cases), with septic complications (20% in diabetics compared to 7.8% in non-diabetics) or cholestasis (20% in diabetics v. 15.8% in non-diabetics). These figures indicate that all diabetics and especially the elderly should be subjected to careful examination to identify any bile disorders.


[Serum levels of 25-hydroxycholecalciferol (25-OH-D3) in children of different age groups (author's transl)].
Serum 25-OH-D3 levels were determined in 78 children aged 6 weeks to 15 years, in March 1977 and March 1978 in Vienna. The total number of probands was divided into age groups, each comprising a range of 3 years. The average value with 1 SD. found over the whole age range was 48.3 +/- 25.75 nmol/l (i.e. 19.4 +/- 10.34 ng/ml). Somewhat higher levels were found in the age groups 3 to 6 and 6 to 9 years, with a slight decrease in the later age groups, but no significant differences were detected. The obtained values seem to represent the "normal" 25-OH-D3 serum levels of our population in the above-mentioned age range.


Emerging therapies in neurorehabilitation.
Just as advancing technology has furthered our understanding of how the nervous system recovers, technology also enables the development of novel approaches to treatment. Because nervous system disease and injury often lead to severely impaired function, patients and families are willing to try anything, so therapies are often adopted with little evidence that they actually work. Evidence shows that comprehensive rehabilitation programs produce better outcomes, but it is still not understood what components of these multifaceted programs are critical to their success. Functional neuroimaging and other modalities now allow monitoring of neurophysiologic changes that can be paired with assessments detailing clinical changes, furthering our understanding of the factors that influence the recovery process. This article discusses several novel and emerging therapies in neurorehabilitation as well as recent multistudy reviews of selected treatments.


The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA.
A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers. The physical determinants of the conformational landscape are found to be predominantly steric interactions within the dinucleotide backbone, with medium-dependent backbone-base electrostatic interactions serving to tune the relative stability of the different local energy minima. The fidelity of the PES to duplex DNA properties is validated through a correspondence to the conformational distribution of duplex DNA crystal structures and the reproduction of observed sequence specific propensities for the formation of A-form DNA. The utility of the PES is demonstrated through its succinct and accurate description of complex conformational processes in simulations of duplex DNA. The study suggests that stereochemical considerations of the nucleic acid backbone play a role in determining conformational preferences of DNA which is analogous to the role of local steric interactions in determining polypeptide secondary structure.


Effect of Memantine on Serum Levels of Neuron-Specific Enolase and on the Glasgow Coma Scale in Patients With Moderate Traumatic Brain Injury.
Traumatic brain injury (TBI) is a major cause of disability and death globally. Despite significant progress in neuromonitoring and neuroprotection, pharmacological interventions have failed to generate favorable results. We examined the effect of memantine on serum levels of neuron-specific enolase (NSE), a marker of neuronal damage, and the Glasgow Coma Scale (GCS) in patients with moderate TBI. Patients were randomly assigned to the control group (who received standard TBI management) and the treatment group (who, alongside their standard management, received enteral memantine 30 mg twice daily for 7 days). Patients' clinical data, GCS, findings of head computed tomography, and serum NSE levels were collected during the study. Forty-one patients were randomized into the control and treatment groups, 19 and 22 patients respectively. Baseline characteristics and serum NSE levels were not significantly different between the 2 groups. The mean serum NSE levels for the memantine and the control groups on day 3 were 7.95 ± 2.86 and 12.33 ± 7.09 ng/mL, respectively (P = .05), and on day 7 were 5.03 ± 3.25 and 10.04 ± 5.72 ng/mL, respectively (P = .003). The mean GCS on day 3 was 12.3 ± 2.0 and 10.9 ± 1.9 in the memantine and control groups, respectively (P = .03). Serum NSE levels and GCS changes were negatively correlated (r = -0.368, P = .02). Patients with moderate TBI who received memantine had significantly reduced serum NSE levels by day 7 and marked improvement in their GCS scores on day 3 of the study.


Predicting freezing for some repulsive potentials.
We propose a simple method to approximately predict the freezing (fluid-solid) phase transition in systems of particles interacting via purely repulsive potentials. The method is based on the striking universality of the freezing curve for the model Yukawa and inverse-power-law interactions. This method is applied to draw an exemplary phase diagram of complex plasmas. We suggest that it can also be used to locate freezing transition in other substances with similar properties of interaction.


[Familial summer-type hypersensitivity pneumonitis in a husband and wife].
We encountered a family in which two of four members, the husband and his wife, had summer-type hypersensitivity pneumonitis at the same time, about two months after they moved to the residence. A 45-year-old man had cough, fever and exertional dyspnea. Chest computed tomography showed diffuse centriloblar ground-glass attenuation in both lung fields. His 43-year-old wife had chest small nodular shadows and similar symptoms to his husband. Serum anti-Tricosporon cutaneum (T. asahi: serotype II and T. mucoides: serotype I) antibodies of both patients were at the positive level. They were given diagnosis as summer-type hypersensitivity pneumonitis by radiological, serological and histological examinations. The symptoms in both cases were improved immediately after administration of systemic corticosteroid. Summer-type hypersensitivity pneumonitis was assumed to be caused for about two months duration of expousure to antigen.


Silencing of RNA helicase II/Gualpha inhibits mammalian ribosomal RNA production.
The intricate production of ribosomal RNA is well defined in yeast, but its complexity in higher organisms is barely understood. We recently showed that down-regulation of nucleolar protein RNA helicase II/Gualpha (RH-II/Gualpha or DDX21) in Xenopus oocytes inhibited processing of 20 S rRNA to 18 S and contributed to degradation of 28 S rRNA (Yang, H., Zhou, J., Ochs, R. L., Henning, D., Jin, R., and Valdez, B. C. (2003) J. Biol. Chem. 278, 38847-38859). Since no nucleolar RNA helicase has been functionally characterized in mammalian cells, we used short interfering RNA to search for functions for RH-II/Gualpha and its paralogue RH-II/Gubeta in rRNA production. Silencing of RH-II/Gualpha by more than 80% in HeLa cells resulted in an almost 80% inhibition of 18 and 28 S rRNA production. This inhibition could be reversed by exogenous expression of wild type RH-II/Gualpha. A helicase-deficient mutant form having ATPase activity was able to rescue the production of 28 S but not 18 S rRNA. A phenotype exhibiting inhibition of 18 S and 28 S rRNA production was also observed when the paralogue RH-II/Gubeta was overexpressed. Both down-regulation of RH-II/Gualpha and overexpression of RH-II/Gubeta slowed cell proliferation. The opposite effects of the two paralogues suggest antagonistic functions.


Comparison of the Health Status of Vegetarians and Omnivores Based on Biochemical Blood Tests, Body Composition Analysis and Quality of Nutrition.
Many vegetarians are motivated by the health aspect of starting a plant-based diet. This diet can offer many health benefits. The study aimed to check whether people on a vegetarian diet are in good health, have a good nutritional intake, and follow the principles of healthy eating compared with omnivores. Twenty-two vegetarians on a vegetarian diet for more than five years and 22 omnivores aged 18-45 were interviewed. Each of them was given a food questionnaire, body composition analysis (BIA), and biochemical blood analysis, and their 7-day diet was analyzed. Polish vegetarians exhibit similar health statuses and tend towards better health than omnivores. They have an adequate body composition. Biochemical blood analysis showed no significant differences in blood parameters between vegetarians and omnivores, despite specific deficiencies such as vitamin B12, vitamin D and elevated homocysteine levels in vegetarians. They have a better nutritional status and follow good dietary principles. However, they were more likely to consume alcohol, add salt to their meals and sweeten hot drinks. In addition, the lifestyle of vegetarians can be described as healthier, as they are more likely to engage in leisure-time physical activity and get enough sleep.


Use of whole genome shotgun metagenomics: a practical guide for the microbiome-minded physician scientist.
Whole genome shotgun sequencing (WGS) has been increasingly recognized as the most comprehensive and robust approach for metagenomics research. When compared with 16S-based metagenomics, it offers the advantage of identification of species level taxonomy and the estimation of metabolic pathway activities from human and environmental samples. Several large-scale metagenomic projects have been recently conducted or are currently underway utilizing WGS. With the generation of vast amounts of data, the bioinformatics and computational analysis of WGS results become vital for the success of a metagenomics study. However, each step in the WGS data analysis, including metagenome assembly, gene prediction, taxonomy identification, function annotation, and pathway analysis, is complicated by the shear amount of data. Algorithms and tools have been developed specifically to handle WGS-generated metagenomics data with the hope of reducing the requirement on computational time and storage space. Here, we present an overview of the current state of metagenomics through WGS sequencing, challenges frequently encountered, and up-to-date solutions. Several applications that are uniquely applicable to microbiome studies in reproductive and perinatal medicine are also discussed.


AppppA, heat-shock stress, and cell oxidation.
Salmonella typhimurium LT2 induces a set of heat-shock proteins analogous to those found previously in Escherichia coli. These are virtually the only proteins synthesized after a temperature shift from 28 degrees C to 50 degrees C. Using a two-dimensional thin-layer chromatographic system developed to resolve adenylylated nucleotides, we have found that S. typhimurium and E. coli accumulate P1,P4-diadenosine-5'-tetraphosphate (AppppA), P1-(adenosine-5')-P3-(guanosine-3'-diphosphate-5')-triphosphate (ApppGpp), P1-(adenosine-5')-P4-(guanosine-5')-tetraphosphate (AppppG), P1-(adenosine-5')-P3-(guanosine-5')-triphosphate (ApppG), and P1,P3-diadenosine-5'-triphosphate (ApppA) after heat shock. These same adenylylated nucleotides accumulate after exposure to ethanol, an agent also known to induce the heat-shock response in a variety of cells. AppppA, ApppGpp, AppppG, ApppG, and ApppA were previously shown to accumulate under conditions of oxidation stress. We proposed that these adenylylated nucleotides may be alarmones--i.e., regulatory molecules, alerting cells to the onset of oxidation stress. The finding that these dinucleotides accumulate in response to heat shock suggests that oxidation and heat shock have a common physiological effect on cells. We hypothesize that these dinucleotides signal the onset of these stresses and trigger the "heat-shock response."


Use of the ''Polymerase Chain Reaction'' for the diagnosis of Helicobacter pylori infection.
H. pylori infection can be diagnosed by means of non-invasive tests or invasive techniques using endoscopy. The choice of the test depends on available instruments, type of diseases, aim of diagnostic research (therapeutic or epidemiological) and test features. PCR is able to reveal pathogenic germs in biological material with very high sensitivity and specificity. In vitro DNA amplification method consists of hybriding denaturated DNA by means of two oligonucleotide primers that allow to copy DNA fragment. The aim of our study was to determine, using PER, H. pylori colonization in the gastric mucosa of 18 consecutive patients under-went gastroscopy. Eighteen patients complaining of dyspeptic symptoms and referred to us for upper GI endoscopy participated in the study. The studied population comprised 9 males and 9 females with mean age of 55.4 yrs (range 26-73 years). All patients underwent gastroscopy during which 4 biopsies from the antrum and 4 from the corpus were obtained for Giemsa stain, PCR analysis and histologic examination. A pair of synthetic oligonucleotides for H. pylori urease A gene, designated as HPU1 and HPU2, were used. Urease A gene fragment amplified by PCR was analyzed by 1.5 agarose gel electrophoresis. Positivity for H. pylory corresponded to PCR DNA products migrating at 411 bp after staining with ethidium bromide. The patients were divided into two groups, according to H. pylori infection, determined by means of Giemsa stain: group A, comprising 11 H. pylori-positive patients; and group B, with 7 H. pylori-negative patients. Our PCR assay of gastric mucosa samples proved positive in 7 cases of group A (63.6%), whereas it always proved negative among group B subjects (100%). Our findings, apparently in contrast with the high sensitivity of PCR, may be attributed to the lower specificity of histology or, alternatively, the absence of H. pylori in the samples tested by PCR due to the patchy distribution of H. pylori colonization in the gastric mucosa. These observations are in agreement with those from other investigations.


"From molecular to clinic": The pivotal role of CDC42 in pathophysiology of human papilloma virus related cancers and a correlated sensitivity of afatinib.
Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic interventions. Bioinformatics empowered us to investigate these cancers from new entry points. DNA methylation data of cervical squamous cell carcinoma (CESC) and anal squamous cell carcinoma (ASCC) were analyzed to identify the significantly altered pathways. Through analyses integrated with RNA sequencing data of genes in these pathways, genes with strongest correlation to the TNM staging of CESC was identified and their correlations with overall survival in patients were assessed. To find a potential promising drug, correlation analysis of gene expression levels and compound sensitivity was performed. In vitro experiments were conducted to validate these findings. We further performed molecular docking experiments to explain our findings. Significantly altered pathways included immune, HPV infection, oxidative stress, ferroptosis and necroptosis. 10 hub genes in these pathways (PSMD11, RB1, SAE1, TAF15, TFDP1, CORO1C, JOSD1, CDC42, KPNA2 and NUP62) were identified, in which only CDC42 high expression was statistically significantly correlated with overall survival (Hazard Ratio: 1.6, P = 0.045). Afatinib was then screened out to be tested. In vitro experiments exhibited that the expression level of CDC42 was upregulated in HaCaT/A431 cells transfected with HPV E6 and E7, and the inhibitory effect of afatinib on proliferation was enhanced after transfection. CDC42-GTPase-effector interface-EGFR-afatinib was found to be a stable complex with a highest ZDOCK score of 1264.017. We identified CDC42 as a pivotal gene in the pathophysiology of HPV-related cancers. The upregulation of CDC42 could be a signal for afatinib treatment and the mechanism in which may be an increased affinity of EGFR to afatinib, inferred from a high stability in the quaternary complex of CDC42-GTPase-effector interface-EGFR-afatinib.


Reconstitution of a functional photosynthetic receptor complex with isolated subunits of core light-harvesting complex and reaction centers.
The B820 subunit form of the core light-harvesting complex LHI, isolated from the photosynthetic bacterium Rhodospirillum rubrum, was combined in a reassociation assay with the reaction center (RC) isolated from the same or related bacteria. This reassociation produced a photoreceptor complex (PRC) which appeared, by absorption spectroscopy, circular dichroism measurements, and kinetic absorption spectroscopy measuring transient photochanges, as analogous to the PRC in the intact bacteria. Energy transfer between the LHI and reaction center progressed with almost 100% efficiency and indicated a cooperative pattern of transfer. Treatment of the RC with proteinase K resulted in peptide cleavages of all three polypeptides of the RC but did not alter the light-induced charge separation in the RC or prevent the reassociation of the LHI and modified RC. Energy transfer efficiency from LHI to RC still approached 100% but the cooperative behavior seen in reconstitutions with the intact RC was not observed. Initial experiments using interspecies reassociations (LHI from Rhodobacter sphaeroides and RC from Rs. rubrum) showed a low efficiency of energy transfer from LHI to RC. Possible association domains for the LHI-RC interaction based on considerations of the comparative amino acid sequences of the RC of each bacteria and the most feasible remaining residues in the proteinase K treated RC are considered.


Drug sorption to glass and plastics.
The general properties of glass and plastics, the main packaging materials for pharmaceutical products, are described. The use of plastic materials in medicine and pharmaceutical packaging has increased considerably in the last decade, but research on drug/plastics interactions has to a certain extent lagged behind. This review draws together much of the current information on drug/plastic interactions, discussing mechanisms of drug-binding to plastic materials and highlighting potential problems arising from the use of plastic containers, or use of cellulose ester filters for clarification or sterilisation of drug solutions.


Bioinspired Materials: From Living Systems to New Concepts in Materials Chemistry.
Nature successfully employs inorganic solid-state materials (i.e., biominerals) and hierarchical composites as sensing elements, weapons, tools, and shelters. Optimized over hundreds of millions of years under evolutionary pressure, these materials are exceptionally well adapted to the specifications of the functions that they perform. As such, they serve today as an extensive library of engineering solutions. Key to their design is the interplay between components across length scales. This hierarchical design-a hallmark of biogenic materials-creates emergent functionality not present in the individual constituents and, moreover, confers a distinctly increased functional density, i.e., less material is needed to provide the same performance. The latter aspect is of special importance today, as climate change drives the need for the sustainable and energy-efficient production of materials. Made from mundane materials, these bioceramics act as blueprints for new concepts in the synthesis and morphosynthesis of multifunctional hierarchical materials under mild conditions. In this review, which also may serve as an introductory guide for those entering this field, we demonstrate how the pursuit of studying biomineralization transforms and enlarges our view on solid-state material design and synthesis, and how bioinspiration may allow us to overcome both conceptual and technical boundaries.


Complexes of C60 with cyclic oligothiophenes: a theoretical study.
Complexes of C60 and cyclic and linear oligothiophenes containing 8 and 12 repeating units have been modeled at the M05-2X/6-311G**//M05-2X/6-31G* level of theory. BSSE-corrected binding energies of neutral donor-acceptor complexes vary from 5 to 12 kcal/mol depending on the complex and donor type. Inclusion complexes formed by C60 and cyclooligothiophenes containing 8 repeating units were found to be the most stable ones. Only weak charge transfer from oligothiophene to C60 fragment (<0.1 electron) is observed in the ground state, whereas complete electron transfer from oligothiophene fragment to C60 has been found in the excited state. One electron oxidation or reduction increases binding energies of "tight" complexes and decreases donor-acceptor interaction for "loose" complexes. In the case of cation radicals, positive charge is totally concentrated at the oligothiophene fragment, whereas in anion radicals, negative charge is located at the C60 moiety. Calculations demonstrated that plane oligothiophene conformation and weak binding in a donor-acceptor complex favor the photoinduced charge-carrier formation.


Endothelial Nitric Oxide Synthase (-786T>C) and Endothelin-1 (5665G>T) Gene Polymorphisms as Vascular Dysfunction Risk Factors in Sickle Cell Anemia.
Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS -786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM-1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS). The multivariate analysis suggested the influence of the ET-1 gene on ACS outcome and an association of the eNOS gene with upper respiratory tract infection. We suggest that eNOS and ET-1 gene polymorphisms can influence SCA pathophysiology and that eNOS variant in SCA patients might be important to nitric oxide activity and vascular alteration. We found an association of the ET-1 minor allele in ACS, showing the importance of genetic screening in SCA.


Service-learning from the views of university teachers: a qualitative study based on focus groups.
Under the New Undergraduate Curriculum at The Hong Kong Polytechnic University (PolyU), students are required to take a 3-credit subject to fulfill service-learning requirements. To understand the views of teachers regarding service-learning, five focus group interviews (n=33) are conducted to examine the perceived characteristics and myths of service-learning as well as colleagues' views on the policy at PolyU. Results showed that most informants are aware of service-learning and have seen its benefits to both students and teachers. Most informants also possess positive views about service-learning. Nevertheless, in terms of service-learning at PolyU, three different groups of views on service-learning are observed, namely, positive, negative, and mixed views. This paper also discusses teachers' views on the anticipated difficulties of service-learning implementation and the ways, by which to promote the subject in the PolyU context.


Effects of Ambient Air Pollution Exposure on Olfaction: A Review.
Olfactory dysfunction affects millions of people worldwide. This sensory impairment is associated with neurodegenerative disease and significantly decreased quality of life. Exposure to airborne pollutants has been implicated in olfactory decline, likely due to the anatomic susceptibility of the olfactory nerve to the environment. Historically, studies have focused on occupational exposures, but more recent studies have considered effects from exposure to ambient air pollutants. To examine all relevant human data evaluating a link between ambient pollution exposure and olfaction and to review supporting animal data in order to examine potential mechanisms for pollution-associated olfactory loss. We identified and reviewed relevant articles from 1950 to 2015 using PubMed and Web of Science and focusing on human epidemiologic and pathophysiologic studies. Animal studies were included only to support pertinent data on humans. We reviewed findings from these studies evaluating a relationship between environmental pollutant exposure and olfactory function. We identified and reviewed 17 articles, with 1 additional article added from a bibliography search, for a total of 18 human studies. There is evidence in human epidemiologic and pathologic studies that increased exposure to ambient air pollutants is associated with olfactory dysfunction. However, most studies have used proxies for pollution exposure in small samples of convenience. Human pathologic studies, with supporting animal work, have also shown that air pollution can contact the olfactory epithelium, translocate to the olfactory bulb, and migrate to the olfactory cortex. Pollutants can deposit at each location, causing direct damage and disruption of tissue morphology or inducing local inflammation and cellular stress responses. Ambient air pollution may impact human olfactory function. Additional studies are needed to examine air pollution-related olfactory impacts on the general population using measured pollution exposures and to link pollution exposure with olfactory dysfunction and related pathology. Citation: Ajmani GS, Suh HH, Pinto JM. 2016. Effects of ambient air pollution exposure on olfaction: a review. Environ Health Perspect 124:1683-1693; http://dx.doi.org/10.1289/EHP136.


Mutations in circularly permuted GTPase family genes AtNOA1/RIF1/SVR10 and BPG2 suppress var2-mediated leaf variegation in Arabidopsis thaliana.
Leaf variegation mutants constitute a unique group of chloroplast development mutants and are ideal genetic materials to dissect the regulation of chloroplast development. We have utilized the Arabidopsis yellow variegated (var2) mutant and genetic suppressor analysis to probe the mechanisms of chloroplast development. Here we report the isolation of a new var2 suppressor locus SUPPRESSOR OF VARIEGATION (SVR10). Genetic mapping and molecular complementation indicated that SVR10 encodes a circularly permuted GTPase that has been reported as Arabidopsis thaliana NITRIC OXIDE ASSOCIATED 1 (AtNOA1) and RESISTANT TO INHIBITION BY FOSMIDOMYCIN 1 (RIF1). Biochemical evidence showed that SVR10/AtNOA1/RIF1 likely localizes to the chloroplast stroma. We further demonstrate that the mutant of a close homologue of SVR10/AtNOA1/RIF1, BRASSINAZOLE INSENSITIVE PALE GREEN 2 (BPG2), can also suppress var2 leaf variegation. Mutants of SVR10 and BPG2 are impaired in photosynthesis and the accumulation of chloroplast proteins. Interestingly, two-dimensional blue native gel analysis showed that mutants of SVR10 and BPG2 display defects in the assembly of thylakoid membrane complexes including reduced levels of major photosynthetic complexes and the abnormal accumulation of a chlorophyll-protein supercomplex containing photosystem I. Taken together, our findings suggest that SVR10 and BPG2 are functionally related with VAR2, likely through their potential roles in regulating chloroplast protein homeostasis, and both SVR10 and BPG2 are required for efficient thylakoid protein complex assembly and photosynthesis.


Multivitamin-Induced Pharmacobezoar: A Rare Entity of Large Bowel Obstruction.
The term bezoar refers to a foreign object found like a mass of concretion in the gastrointestinal tract that results from an accumulation of undigested material. When the composition of the ingested material is a medication, it is known as a pharmacobezoar. A rare complication from pharmacobezoar is large intestinal obstruction. Here we present the case of a 77-year-old male who presented with progressive abdominal distension, involuntary guarding, and large bowel obstruction. Abdominal imaging studies were remarkable for radiopaque objects of uncertain etiology in the transverse colon and rectal ampulla. The patient underwent colonic decompression by sigmoidoscopy, where the pills were identified by direct visualization. He later underwent endoscopic removal of the pharmacobezoars. A detailed medication review identified the culprit to be multivitamins. This case portrays an unusual etiology of large bowel obstruction. At this moment, no cases have been reported of multivitamins as the culprit of pharmacobezoar with subsequent development of large bowel obstruction.


The challenge of vaccinating adults: attitudes and beliefs of the Canadian public and healthcare providers.
Vaccine coverage for recommended vaccines is low among adults. The objective of this study was to assess the knowledge, attitudes, beliefs and behaviours of adults and healthcare providers related to four vaccine-preventable diseases and vaccines (diphtheria-tetanus-pertussis, zoster, pneumococcus and influenza). We undertook a survey and focus groups of Canadian adults and healthcare providers (doctors, nurses, pharmacists). A total of 4023 adults completed the survey and 62 participated in the focus groups; 1167 providers completed the survey and 45 participated in the focus groups. Only 46.3% of adults thought they were up-to-date on their vaccines; 30% did not know. In contrast, 75.6% of providers reported being up-to-date. Only 57.5% of adults thought it was important to receive all recommended vaccines (compared to 87.1-91.5% of providers). Positive attitudes towards vaccines paralleled concern about the burden of illness and confidence in the vaccines, with providers being more aware of disease burden and confident in vaccine effectiveness than the public. Between 55.0% and 59.7% of adults reported willingness to be vaccinated if recommended by their healthcare provider. However, such recommendations were variable; while 77.4% of the public reported being offered and 52.8% reported being recommended the influenza vaccine by their provider, only 10.8% were offered and 5.6% recommended pertussis vaccine. Barriers and facilitators to improved vaccine coverage in adults, such as trust-mistrust of health authorities, pharmaceutical companies and national recommendations, autonomy versus the public good and logistical issues (such as insufficient time and lack of vaccination status tracking), were identified by both the public and providers. Despite guidelines for adult vaccination, there are substantial gaps in knowledge and attitudes and beliefs among both the public and healthcare providers that lead to low vaccine coverage. A systematic approach that involves education, elimination of barriers and establishing and improving infrastructure for adult immunisation is required.


Use of financial reports in managing pharmacies.
The use of financial reports for preparing and monitoring the pharmacy budget is reviewed. Internal reports are generated within the department or hospital and are used to compare actual financial performance with budgeted projections. External reports are usually prepared by outside agencies and are used to compare the productivity, operations, and financial performance of one hospital with others in a predetermined group. The level of detail used in preparing financial reports determines the level of detail that can be used to monitor the budget. Internal reports on revenue, nonlabor expense, and labor expense are discussed, and the limitations of external reports comparing hospitals are presented. Effective use of financial reports is important in accurate budget forecasting, and pharmacy managers must seek out the financial information that will be of most value to them.


Cardiovascular disease in women with HIV-1 infection.
Cardiovascular disease is a leading cause of death in women, nevertheless it is often underestimated in female patients without overt risk factors. The chronic infection by Human Immunodeficiency Virus (HIV) is clearly associated, along with the use of certain antiretroviral drugs and traditional risk factors, with an increased risk of cardiovascular diseases. The aim of this manuscript is to review the epidemiology, risk factors, pathogenesis, diagnostic approach, primary and secondary prevention strategies of cardiovascular disease in HIV-negative and HIV-positive female subjects. The ultimate goal is to promote knowledge and development of specific and appropriate clinical interventions and guidelines in this group of high-risk patients, mostly in view of the expected growth of ageing females with HIV.


[Channel Selection for Multi-class Motor Imagery Based on Common Spatial Pattern].
High-density channels are often used to acquire electroencephalogram (EEG) spatial information in different cortical regions of the brain in brain-computer interface (BCI) systems. However, applying excessive channels is inconvenient for signal acquisition, and it may bring artifacts. To avoid these defects, the common spatial pattern (CSP) algorithm was used for channel selection and a selection criteria based on norm-2 is proposed in this paper. The channels with the highest M scores were selected for the purpose of using fewer channels to acquire similar rate with high density channels. The Dataset III a from BCI competition 2005 were used for comparing the classification accuracies of three motor imagery between whole channels and the selected channels with the present proposed method. The experimental results showed that the classification accuracies of three subjects using the 20 channels selected with the present method were all higher than the classification accuracies using all 60 channels, which convinced that our method could be more effective and useful.


Cochlear Implantation in Elderly Patients: Survival Duration, Hearing Outcomes, Complication Rates, and Cost Utility.
The prevalence of hearing loss and its consequences is increasing as the elderly population grows. As the guidelines for cochlear implantation (CI) expand, the number of elderly CI recipients is also increasing. We report complication rates, survival duration, and audiological outcomes for CI recipients aged 80 years and over and discuss the cost utility of CI in this age group. A retrospective cohort study was undertaken of all CI recipients (126 cases), aged 80 years and over at the time of their surgery, implanted at our institution (Cambridge University Hospitals) during a period from January 1, 2001, to March 31, 2019. Data on survival at 1, 3, and 5 years post-implantation, post-operative complications and functional hearing outcomes including audiometric and speech discrimination outcomes (Bamford-Kowal-Bench sentence test) have been reported. The mean age at implantation was 84 years. The mean audiometric score improved from 108 dB HL to 28 dB HL post-implantation. The mean Bamford-Kowal-Bench score improved from 14% to 66% and 73% at 2 and 12 months post-implantation, respectively. The complication rate was 15.3%. The survival probability at 1 year post-implantation was 0.95 for females and 0.93 for males, at 3 years was 0.89 for females and 0.81 for males, and at 5 years was 0.74 for females and 0.54 for males. CI is safe and well-tolerated in this age group and elderly patients gain similar audiometric and functional benefit as found for younger age groups.


New Insights into the Crosstalk between NMDARs and Iron: Implications for Understanding Pathology of Neurological Diseases.
Both iron dyshomeostasis and N-methyl-D-aspartate receptors (NMDARs)-mediated neurotoxicity have been shown to have an important role in neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence proved that activation of NMDARs could promote iron overload and iron-induced neurotoxicity by enhancing iron importer divalent metal transporter 1 (DMT1)-mediated iron uptake and iron releasing from lysosome. Also, iron overload could regulate NMDARs-mediated synaptic transmission. This indicates that there might be a possible relationship between iron and activation of NMDARs in neurological diseases. Understanding this interaction between iron and activation of NMDARs may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for these diseases. Therefore, in this review article, we will describe the dysfunction of iron metabolism and NMDARs in neurological diseases including PD and AD, and summarize the new insight into the mechanisms underlying the interaction between iron and activation of NMDARs.


Post-traumatic plasminogenesis in intraarticular exudate in the knee joint.
Intraarticular exudate, observed in the knee joint a few weeks after a traumatic incident, is one of post-traumatic complications. Evacuation of the exudate prevents damage of the articular cartilage by the fluid possessing potent proteolytic properties. In view of the lack of data concerning the role of the fibrinolysis system in proteolytic destructive processes induced by the exudate, the aim of the study was to find out whether plasmin is present in the post-traumatic intraarticular exudate and whether it is generated in connection with excessive plasminogen activator levels or deficiency of plasminogen activator inhibitors in the synovial fluid. 55 patients (mean age 35.1), with history of knee joint traumas and exudate appearing in the joint at least 3 weeks post-traumatically. The patients and 30 healthy controls were subjected to the following tests of the synovial fluid and plasma: the levels of tissue plasminogen activator, type 1 plasminogen activator inhibitor, plasmin-alpha 2-antiplasmin complexes, fibrinogen and von Willebrand factor antigen, the activity of urokinase plasminogen activator, prekallikrein, alpha-2-antiplasmin, C1 inhibitor, type 1 plasminogen activator inhibitor, euglobulin clot lysis time. The patients' plasma demonstrated significantly higher levels of fibrinogen and PAP complexes, and decreased u-PA activity in comparison in that obtained from the controls. Significantly higher levels of PAP complexes and u-PA antigen were found in the exudate than in the patients' plasma. Local, intraarticular plasmin generation, probably u-PA-dependent, occurs in knee joint exudate. Plasminogen activator inhibitors are probably not very closely associated with increased intraarticular plasminogenesis.


[Trachea-bronchoplasty in the surgical treatment of locally advanced non-small cell lung cancer].
Some of the locally advanced non-small cell lung cancer (NSCLC) need different trachea-bronchoplasty operative styles in order to make the widest possible to resect the tumor and remain normal pulmonary function. The aim of this study is to explore the surgical problem during trachea-bronchoplasty operation. There were 2206 patients with NSCLC underwent surgical treatment from January 2003 to June 2005 in this hospital. Of the 2206 cases, 100 patients accepted the trachea-bronchoplasty, whose clinic data were analyzed. There were 42 cases of squamous cell carcinoma, 23 adenosquamous carcinoma, 11 adenocarcinoma, 5 mucoepidermoid carcinoma, 4 adeoid cystic carcinoma, 3 carcinoid and 12 undetermined. Thirty-four cases were in stage IB, 23 in stage IIB, 23 in stage IIIA and 20 in stage IIIB. There were 42 cases of right upper sleeve lobectomy, 1 right lower sleeve lobectomy, 24 left upper sleeve lobectomy, 4 left lower sleeve lobectomy, 8 sleeve bilobectomy, 17 carinal reconstruction, 4 sleeve lobectomy plus pulmonary artery angioplasty. Complete resection (R0) of the cancer was performed in 97 patients and uncomplete resection (margin positive, R1) was performed in 3 patients. Postoperative complication happened in 5 cases (the occurrence rate was 5%): Pneumonia in 2 cases, pleura cavity infection in 1 case, broncho-pleura fistula in 1 case, alveoli-pleura fistula in 1 case. One patient died of pulmonary infection, the operative mortality was 1%. The postoperative inpatient time was from 4 days to 27 days, with median of 11 days. Trachea-bronchoplasty is suitable for some patients of the locally advanced NSCLC and consistent to the tumor surgical treatment principle. A satisfactory cure effect can be obtained for undergoing such operative style. The key point of successful operation is the operating skill to manage trachea, bronchi and pulmonary vessels.


Pembrolizumab-Induced Fatal Myasthenia, Myocarditis, and Myositis in a Patient with Metastatic Melanoma: Autopsy, Histological, and Immunohistochemical Findings-A Case Report and Literature Review.
Immune checkpoint inhibitors (ICIs) represent a major advance in cancer treatment. The lowered immune tolerance induced by ICIs brought to light a series of immune-related adverse events (irAEs). Pembrolizumab belongs to the ICI class and is a humanized IgG4 anti-PD-1 antibody that blocks the interaction between PD-1 and PD-L1. The ICI-related irAEs involving various organ systems and myocarditis are uncommon (incidence of 0.04% to 1.14%), but they are associated with a high reported mortality. Unlike idiopathic inflammatory myositis, ICI-related myositis has been reported to frequently co-occur with myocarditis. The triad of myasthenia, myositis, and myocarditis must not be underestimated as they can rapidly deteriorate, leading to death. Herein we report a case of a patient with metastatic melanoma who fatally developed myasthenia gravis, myocarditis, and myositis, after a single cycle of pembrolizumab. Considering evidence from the literature review, autopsy, histological, and immunohistochemical investigations on heart and skeletal muscle are presented and discussed, also from a medical-legal perspective.


Scale-dependent colocalization in a population of gyrotactic swimmers.
We study the small scale clustering of gyrotactic swimmers transported by a turbulent flow, when the intrinsic variability of the swimming parameters within the population is considered. By means of extensive numerical simulations, we find that the variety of the population introduces a characteristic scale R^{*} in its spatial distribution. At scales smaller than R^{*} the swimmers are homogeneously distributed, while at larger scales an inhomogeneous distribution is observed with a fractal dimension close to what observed for a monodisperse population characterized by mean parameters. The scale R^{*} depends on the dispersion of the population and it is found to scale linearly with the standard deviation both for a bimodal and for a Gaussian distribution. Our numerical results, which extend recent findings for a monodisperse population, indicate that in principle it is possible to observe small scale, fractal clustering in a laboratory experiment with gyrotactic cells.


Switching from warfarin to direct-acting oral anticoagulants: it is time to move forward!
Oral vitamin K antagonists (VKAs), warfarin, have been in routine clinical use for almost 70 years for various cardiovascular conditions. Direct-Acting Oral Anticoagulants (DOACs) have emerged as competitive alternatives for VKAs to prevent stroke in patients with non-valvular atrial fibrillation (AF) and have become the preferred choice in several clinical indications for anticoagulation. Recent guidelines have limited the use of DOACs to patients with non-valvular AF to reduce the risk of cardioembolic complications and to treat venous thromboembolism (VTE). Although emerging evidence is suggestive of its high efficacy, there was a lack of data to support DOACs safety profile in patients with mechanical valve prosthesis, intracardiac thrombi, or other conditions such as cardiac device implantation or catheter ablation. Therefore, several clinical trials have been conducted to assess the beneficial effects of using DOACs, instead of VKAs, for various non-guideline-approved indications. This review aimed to discuss the current guideline-approved indications for DOACs, advantages, and limitations of DOACs use in various clinical indications highlighting the potential emerging indications and remaining challenges for DOACs use. Several considerations are in favour of switching from warfarin to DOACs including superior efficacy, better adverse effect profile, fewer drug-drug interactions, and they do not require frequent international normalized ratio (INR) monitoring. Large randomized controlled trials are required to determine the safety and efficacy of their use in various clinical indications.


[Vascularization of the matrix of hyaline rib cartilage in the human: changes with increasing age].
A correlative light microscopic/transmission electron microscopic study was performed on human hyaline costal cartilage material of variable age (group I: first postnatal month; group II: second decade, and group III: fifth, sixth and seventh decades of life; total: nine cartilage samples) in order to clarify and evaluate the existence and dimensions of a vascular supply in young hyaline cartilage matrix and to compare with alterations or changes, respectively, occurring with aging. Human postnatal hyaline costal cartilage (4th to 6th rib) is vascularized very early by centripetally running venous/arterial vessels invading from the perichondrium. This process seems to be an active one since endothelial spurs and capillary sprouts could be demonstrated. During the middle decades of life a drastic/substantial decrease in amount/appearance of vessels or vascular supply, respectively, of the cartilage generally seems to occur. From the third/fourth decade on up to higher decades neovascularization seems to be a constant finding, especially in degeneration areas: so-called marrow spaces of cartilage matrix. With increasing age the fibrillar perivascular matrix becomes thicker, resulting in a so-called collagen-collar which consists of highly oriented collagen fibrils/fibers (as compared with the attaching extracellular cartilaginous matrix), most probably newly synthesized by (mesenchymal/fibrocytic/specialized?) cells accompanying the invading vessels. Incidence and possible function of the structures found in aged human costal cartilage are not fully understood; the ultrastructural changes compared with postnatal costal cartilage, however, are evident and demonstrated.


GPR40 reduces food intake and body weight through GLP-1.
G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.


[Proper use of antidepressants in the acute and maintenance phase treatment of depression].
In spite of their different pharmacological profiles, a number of meta-analyses have shown that all antidepressants are equally effective in the treatment of major depression. However, there is the discordance between efficacy data and clinical observation. So then, how should we use antidepressants properly in the clinical setting? Toward rational pharmacotherapy, the selection of antidepressant medications will be based on their pharmacological profiles, clinical features of the patient, the anticipated side effects, and clinical trial data regarding the medication. During about 6 months following remission, the treatment that was effective in the acute phases should be used in the maintenance phase to prevent relapse.


The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease.
Rosenthal fibers (RFs) are cytoplasmic, proteinaceous aggregates. They are the pathognomonic feature of the astrocyte pathology in Alexander Disease (AxD), a neurodegenerative disorder caused by heterozygous mutations in the GFAP gene, encoding glial fibrillary acidic protein (GFAP). Although RFs have been known for many years their origin and significance remain elusive issues. We have used mouse models of AxD based on the overexpression of human GFAP (transgenic, TG) and a point mutation in mouse GFAP (knock-in, KI) to examine the formation of RFs and to find astrocyte changes that correlate with the appearance of RFs. We found RFs of various sizes and shapes. The smallest ones appear as granular depositions on intermediate filaments. These contain GFAP and the small heat shock protein, alphaB-crystallin. Their aggregation appears to give rise to large RFs. The appearance of new RFs and the growth of previously formed RFs occur over time. We determined that DAPI is a reliable marker of RFs and in parallel with Fluoro-Jade B (FJB) staining defined a high variability in the appearance of RFs, even in neighboring astrocytes. Although many astrocytes in AxD with increased levels of GFAP and with or without RFs change their phenotype, only some cells with large numbers of RFs show a profound reconstruction of cellular processes, with a loss of fine distal processes and the appearance of large, lobulated nuclei, likely due to arrested mitosis. We conclude that 1) RFs appear to originate as small, osmiophilic masses containing both GFAP and alphaB-crystallin deposited on bundles of intermediate filaments. 2) RFs continue to form within AxD astrocytes over time. 3) DAPI is a reliable marker for RFs and can be used with immunolabeling. 4) RFs appear to interfere with the successful completion of astrocyte mitosis and cell division.


The plasma concentration of copper and prevalence of depression were positively correlated in shift nurses.
Several studies have reported the prevalence of depression in shift nurses to be 15%, and in some cases it may even be as high as 23%. Depression is a major cause of poor sleep quality and can impede efforts to overcome the chronic fatigue that commonly affects shift nurses. Adverse mental health issues have been confirmed in shift nurses, but few studies have investigated the underlying cause of poor mental health in different shift-nurse populations. Therefore, the aim of this study was to investigate the relationship of serum trace element levels to mental health and the tendency toward depression in shift nurses. We collected blood samples from 90 shift nurses (day, evening, and night shift) who worked in intensive care units and asked them to complete a general data questionnaire as well as the Chinese version of the Beck Depression Inventory, second edition. The night-shift nurses showed mild-to-moderate depression levels, which were significantly higher than those of the control group and other shift nurses. Night-shift nurses also had higher levels of plasma copper, ferritin, interleukin (IL)-6, and alanine aminotransferase (p < .05) than the control group and other nurses. Elevated concentrations of ferritin and IL-6 are considered important markers for the onset of depression. The results of this study suggest that plasma copper concentrations in nurses should be monitored.


Mass transfer in a nanoscale material enhanced by an opposing flux.
Diffusion is known to be quantified by measuring the rate of molecular fluxes in the direction of falling concentration. In contrast with intuition, considering methanol diffusion in a novel type of nanoporous material (MOF ZIF-8), this rate has now been found to be enhanced rather than slowed down by an opposing flux of labeled molecules. In terms of the key quantities of random particle movement, this result means that the self-diffusivity exceeds the transport diffusivity. It is rationalized by considering the strong intermolecular interaction and the dominating role of intercage hopping in mass transfer in the systems under study.


Plasma zinc is an insensitive predictor of zinc status: use of plasma zinc in children with sickle cell disease.
This study was designed to explore the use of plasma zinc in determining zinc deficiency in children with sickle cell disease-SS (SCD-SS) as indicated by a growth response to zinc supplementation. Fasting plasma zinc was assessed in children with SCD-SS (ages 4 to 10 years) who were randomly assigned to receive 10 mg zinc/d in cherry syrup (zinc) or cherry syrup alone (placebo) for 12 months. Evaluations for growth, dietary intake, and other biochemical parameters were made at baseline and 3, 6, and 12 months. Longitudinal mixed effects analysis evaluated differences between groups over 12 months. A total of 38 prepubertal children (20 male and 18 female; 18 zinc and 20 placebo) completed the study (7.1 +/- 1.7 years old). At baseline, plasma zinc was low (< or = 70 microg/dL) in 7 male subjects. Despite the significant increase in height over 12 months (+0.7 cm) with zinc supplementation (p = .019), plasma zinc did not change over the 12 months of study, and there was no association between plasma zinc and linear growth. Those children with low plasma zinc who received zinc supplementation showed improved linear growth. These findings suggest that plasma zinc is an insensitive indicator of zinc status in children with SCD-SS. Children with low plasma zinc will benefit from zinc supplementation. However, some children with normal plasma zinc and poor growth may also have growth-limiting zinc deficiency and exhibit a growth response to zinc supplementation. Although this study focused on children with SCD-SS, results may be generalized to other pediatric clinical illnesses where nutrition-related growth failure is investigated.


Physician knowledge of herbal toxicities and adverse herb-drug interactions.
To determine how knowledgeable physicians are regarding the toxic effects and drug interactions of herbal remedies. An anonymous voluntary demographic survey and 16-question, multiple-choice quiz was distributed at educational meetings of emergency medicine and internal medicine physicians. The primary outcome measures were to determine whether significant associations existed between quiz scores and the amount of clinical experience, or between quiz scores and self-assessed familiarity with the topic of herbal toxicities and adverse herb-drug interactions. A total of 142 surveys and quizzes were completed by 59 attending physicians, 57 resident physicians, and 26 medical students. The mean subject score on the quiz was only slightly higher than would have occurred from random guessing. Neither the amount of the subjects' clinical experience, nor their self-assessed familiarity with herbal toxicities and drug interactions correlated significantly with the score on the quiz. The physicians and medical students surveyed had little training in herbal toxicities and drug interactions. They generally rated their familiarity with these topics as 'poor', and their scores on the quiz bore out this assessment as correct. Educational efforts might improve physician knowledge of the adverse effects of herbal remedies.


Dengue fever complicated by hemophagocytosis.
Dengue is a common acute viral febrile illness in the tropics. Although the usual presentation is that of a self-limiting illness, its complications are protean. We report a 29-year-old man who presented with an acute febrile illness and was diagnosed with dengue hemorrhagic fever. Despite appropriate supportive therapy, the patient initially improved, but subsequently had clinical deterioration. Evaluation revealed features of hemophagocytic lymphohistiocytosis. He was successfully treated with glucocorticoids and had an uneventful recovery. This case adds to the limited adult cases of virus-associated hemophagocytic syndrome in the literature and the need for prompt recognition and treatment of this rare complication.


Experience with deep venous thrombosis and IPG - 200 as a diagnostic aid.
Deep venous thrombosis is a potentially dangerous alteration in the venous hemodynamics of the lower extremities. Clinical diagnosis, at best, is difficult because of the percentage of silent thrombi and the nonspecificity of the signs and symptoms. Noninvasion evaluation is accurate when performed properly. Venography, however, is the most accurate method of diagnosis. Current methods of prophylaxis are many and varied--some controversial. The effects of tourniquets on the venous system is reviewed. The author's experience with the 1PG-200 is presented. Further studies utilizing the 1PG-200 in preoperative versus postoperative evaluation in podiatric surgery are necessary.


Determination of gastric emptying in nonobese diabetic mice.
Animal studies on diabetic gastroparesis are limited by inability to follow gastric emptying changes in the same mouse. The study aim was to validate a nonlethal gastric emptying method in nonobese diabetic (NOD) LtJ mice, a model of type 1 diabetes, and study sequential changes with age and early diabetic status. The reliability and responsiveness of a [(13)C]octanoic acid breath test in NOD LtJ mice was tested, and the test was used to measure solid gastric emptying in NOD LtJ mice and nonobese diabetes resistant (NOR) LtJ mice. The (13)C breath test produced results similar to postmortem recovery of a meal. Bethanechol accelerated gastric emptying [control: 92 +/- 9 min; bethanechol: 53 +/- 3 min, mean half emptying time (T(1/2)) +/- SE], and atropine slowed gastric emptying (control: 92 +/- 9 min; atropine: 184 +/- 31 min, mean T(1/2) +/- SE). Normal gastric emptying (T(1/2)) in nondiabetic NOD LtJ mice (8-12 wk) was 91 +/- 2 min. Aging had differing effects on gastric emptying in NOD LtJ and NOR LtJ mice. Onset of diabetes was accompanied by accelerated gastric emptying during weeks 1-2 of diabetes. Gastric emptying returned to normal by weeks 3-5 with no delay. The [(13)C]octanoic acid breath test accurately measures gastric emptying in NOD LtJ mice, is useful to study the time course of changes in gastric emptying in diabetic NOD LtJ mice, and is able to detect acceleration in gastric emptying early in diabetes. Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice.


Effects of Selenium on Fusarium Growth and Associated Fermentation Products and the Relationship with Chondrocyte Viability.
This study determined the effects of selenium on the growth of Fusarium strains and the effects of products extracted from the fungal cultures on relevant indicators of chondrocytes injury. The results showed that selenium supplementation resulted in differential effects on the mycelial growth of the strains. Levels of the chondrocyte injury indicators, including cell viability, proteoglycan and type II collagen contents and their mRNA expressions, were all reduced to varying degrees when the chondrocytes were incubated with fermentation extracts, the inhibitory effect varied depending on selenium content supplemented to fungal culture media. The results indicated that certain chain relations existed between the content of selenium in the environment, the production of some metabolites by fungi, and the occurrence of chondrocyte damage. The extent of this relationship and the role it plays in Kaschin-Beck disease pathogenesis merit further study.


Liquid-crystalline bisadducts of [60]fullerene.
A second-generation cyanobiphenyl-based dendrimer was used as a liquid-crystalline promoter to synthesize mesomorphic bisadducts of [60]fullerene. Liquid-crystalline trans-2, trans-3, and equatorial bisadducts were obtained by condensation of the liquid-crystalline promoter, which carries a carboxylic acid function, with the corresponding bisaminofullerene derivatives. A monoadduct of fullerene was also prepared for comparative purposes. All the compounds gave rise to smectic A phases. An additional mesophase, which could not be identified, was observed for the trans-2 derivative. The supramolecular organization of the monoadduct derivative is governed by steric constraints. Indeed, for efficient space filling, adequacy between the cross-sectional areas of fullerene (approximately 100 A(2)) and of the mesogenic groups (approximately 22-25 A(2) per mesogenic group) is required. As a consequence, the monoadduct forms a bilayered smectic A phase. The supramolecular organization of the bisadducts is essentially governed by the nature and structure of the mesogenic groups and dendritic core. Therefore, the bisadducts form monolayered smectic A phases. The title compounds are promising supramolecular materials as they combine the self-organizing behavior of liquid crystals with the properties of fullerene.


From "Gut Feeling" to Objectivity: Machine Preservation of the Liver as a Tool to Assess Organ Viability.
The purpose of this review was to summarise how machine perfusion could contribute to viability assessment of donor livers. In both hypothermic and normothermic machine perfusion, perfusate transaminase measurement has allowed pretransplant assessment of hepatocellular damage. Hypothermic perfusion permits transplantation of marginal grafts but as yet has not permitted formal viability assessment. Livers undergoing normothermic perfusion have been investigated using parameters similar to those used to evaluate the liver in vivo. Lactate clearance, glucose evolution and pH regulation during normothermic perfusion seem promising measures of viability. In addition, bile chemistry might inform on cholangiocyte viability and the likelihood of post-transplant cholangiopathy. While the use of machine perfusion technology has the potential to reduce and even remove uncertainty regarding liver graft viability, analysis of large datasets, such as those derived from large multicenter trials of machine perfusion, are needed to provide sufficient information to enable viability parameters to be defined and validated .


Opportunities for teaching and studying medicine in medieval Portugal before the foundation of the University of Lisbon (1290).
This paper discusses where Portuguese physicians studied medicine. The careers of two thirteenth-century physicians, Petrus Hispanus and Giles of Santarem, indicate that the Portuguese travelled abroad to study in Montpellier or Paris. But it is also possible that there were opportunities for study in Portugal itself. Particularly significant in this respect is the tradition of medical teaching associated with the Augustinian house of Santa Cruz in Coimbra and the reference to medical texts found in Coimbra archives. From these sources it can be shown that there was a suitable environment for medical study in medieval Portugal, encouraging able students to further their medical interests elsewhere.


Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.
Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT. Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).


Small Incision Lenticule Extraction (SMILE) for Hyperopia: Optical Zone Centration.
To evaluate optical zone centration of hyperopic small incision lenticule extraction (SMILE). This prospective study of 60 consecutive hyperopic SMILE procedures used the VisuMax femtosecond laser and matched LASIK procedures with the VisuMax and MEL 80 excimer lasers (Carl Zeiss Meditec AG, Jena, Germany). Inclusion criteria were maximum attempted hyperopic meridian of between +1.00 and +7.00 diopters (D) and astigmatism up to 6.00 D. For SMILE, the optical zone was between 6.3 and 6.7 mm, with a 2-mm transition zone. Two LASIK control groups (6.5- and 7-mm optical zone) were generated matched for spherical equivalent treated. In SMILE, the corneal vertex of the coaxially fixating eye was aligned with the vertex of the curved contact glass. In LASIK, the treatment was centered on the coaxially sighted corneal light reflex (first Purkinje image) with the contralateral eye (Seiler method). A tangential (instantaneous) curvature preoperative to 3 months postoperative difference map was generated for each eye. A fixed grid and set of concentric circles were superimposed on the difference map to measure the offset between the optical zone center and corneal vertex (0,0), and vector analysis was used for comparative analysis. Mean attempted spherical equivalent was +5.61 ± 0.96 D (range: +3.20 to +6.50 D) and mean cylinder was -0.96 ± 0.62 D (range: 0.00 to -2.75 D) in the SMILE group. Mean age was 29 ± 7 years (range: 19 to 52 years) in the SMILE group. Mean centration offset was 0.23 ± 0.15 mm (range: 0 to 0.61 mm) for the SMILE group, 0.33 ± 0.14 mm (range: 0.14 to 0.85 mm) for the 6.5-mm LASIK group, and 0.31 ± 0.19 mm (range: 0.05 to 0.85 mm) for the 7-mm LASIK group. The mean centration offset for SMILE was less than that of both LASIK groups (P < .05). Optical zone centration of hyperopic SMILE was found to be similar to eye-tracker-centered hyperopic LASIK with the MEL 80 laser. [J Refract Surg. 2017;33(3):150-156.].


Effects of calcium channel antagonists on Ca2+ transients in rat and canine cardiomyocytes.
First-generation Ca2+ channel antagonists depress myocardial contractility, but many of the newer Ca2+ channel blockers have a high degree of "vascular selectivity". This study compares the effects of the Ca2+ antagonists felodipine, amlodipine, mibefradil, verapamil and nifedipine, and the Ca2+ channel agonist. (S)(-)-Bay K-8644 on Ca2+ transient amplitudes in fura-2/AM-loaded rat and canine ventricular cardiomyocytes. At 10(-11) and 10(-10) M, felodipine increased [Ca2+]i transient amplitudes by 10-25% in field-stimulated fura-2-loaded cells from both species while at 10(-6) M it depressed [Ca2+]i transients by 80%. Mibefradil increased [Ca2+]i transient amplitudes by 16% at 10(-11) and 10(-10) M and decreased the transients by 25% at 10(-6) M. The calcium channel agonist, (S)(-)-Bay K-8644 increased [Ca2+]i transient amplitudes at 10(-10)-10(-6) M (maximally 37% at 10(-7) M) but depressed [Ca2+]i transients by 10% at 10(-5) M. Nifedipine was inhibitory at all concentrations tested (10(-11)-10(-6) M) in canine myocytes, but in rat cells. 10(-10) M nifedipine increased [Ca2+]i transient amplitudes by 37%. All concentrations of verapamil and amlodipine (10(-11)-10(-6) M) depressed [Ca2+]i transients in both rat and canine myocytes. We conclude that: (1) felodipine and mibefradil may be positive rather than negative inotropes at low concentrations, which are therapeutically relevant: and (2) low concentrations of nifedipine may have a positive inotropic effect in the rat but not the dog heart.


[Floating cell cultures of the fetal pancreas].
A simple method for preparing human and animal fetal pancreatic cell cultures has been developed. It is based on enzymatic treatment of the fetal pancreatic tissue with collalitine in combination with microdissection. As a result of subsequent cultivation there form floating cytotypic and organotypic cultures consisting mainly of B cells in different phases of the secretory cycle. The floating cultures prepared by the above-described method produce insulin and can be successfully used in experimental and clinical transplantology.


GABA receptor binding in rat striatum: localization and effects of denervation.
Intrastriatal injection of 2 microgram of kainic acid, a conformationally restricted analogue of glutamate, causes degeneration of GABAergic neurons intrinsic to the striatum while sparing axons of extrinsic neurons terminating in or passing through the region. From 2 to 15 days after striatal lesion with kainate, the sodium-independent binding of [3H]-psi-aminobutyric acid (GABA) to striatal membranes is increased 200% above that of control. Differences in the amount of endogenous GABA contaminating the membrane preparations do not account for the increased receptor binding. Scatchard analysis reveals an increased affinity of the GABA receptor in the kainate-lesioned striatum with no change in the number of binding sites. The subcellular distribution of the receptor as well as the sensitivity of the receptor to several agonists and antagonists is unchanged by the kainate lesion. Ablation of the nigrostriatal dopaminergic pathway by nigral injection of 8 microgram of 6-hydroxydopamine reduces by 22% the specific binding of [3H]GABA in the ipsilateral striatum and attenuates by 33% the increase in GABA receptor binding produced by the striatal kainate lesion. These studies demonstrate that (1) the sodium independent binding sites for GABA in striatum are localized on axons of extrinsic neurons, and (2) the affinity of these receptors for GABA increases in response to GABAergic denervation.


Coalescing traditions-Coalescing people: Community formation in Pannonia after the decline of the Roman Empire.
The decline of the Roman rule caused significant political instability and led to the emergence of various 'Barbarian' powers. While the names of the involved groups appeared in written sources, it is largely unknown how these changes affected the daily lives of the people during the 5th century AD. Did late Roman traditions persist, did new customs emerge, and did both amalgamate into new cultural expressions? A prime area to investigate these population and settlement historical changes is the Carpathian Basin (Hungary). Particularly, we studied archaeological and anthropological evidence, as well as radiogenic and stable isotope ratios of strontium, carbon, and nitrogen of human remains from 96 graves at the cemetery of Mözs-Icsei dűlő. Integrated data analysis suggests that most members of the founder generation at the site exhibited burial practises of late Antique traditions, even though they were heterogeneous regarding their places of origin and dietary habits. Furthermore, the isotope data disclosed a nonlocal group of people with similar dietary habits. According to the archaeological evidence, they joined the community a few decades after the founder generation and followed mainly foreign traditions with artificial skull modification as their most prominent characteristic. Moreover, individuals with modified skulls and late Antique grave attributes attest to deliberate cultural amalgamation, whereas burials of largely different isotope ratios underline the recipient habitus of the community. The integration of archaeological and bioarchaeological information at the individual level discloses the complex coalescence of people and traditions during the 5th century.


Jersey calf performance in response to high-protein, high-fat liquid feeds with varied fatty acid profiles: intake and performance.
The objective of this study was to determine whether altering the fatty acid (FA) profile of milk replacer (MR) with coconut oil, which contains a high concentration of medium-chain FA, to more closely match the FA profile typically found in whole milk from Jersey cows, would improve Jersey calf performance. Male (n=18) and female (n=32) Jersey calves were assigned at birth to 1 of 4 liquid diets: (1) pasteurized Jersey saleable whole milk [pSWM; 27.9% crude protein (CP) and 33.5% fat]; (2) 29.3% CP and 29.1% fat MR, containing 100% of fat as edible lard (100:00); (3) 28.2% CP and 28.0% fat MR, containing 80% of fat as lard and 20% as coconut oil (80:20); and (4) 28.2% CP and 28.3% fat MR, containing 60% of the fat as lard and 40% as coconut oil (60:40). Calves were fed their respective liquid diet twice daily during wk 1 through 7 and once daily until weaning (approximately wk 8). Calves had ad libitum access to grain and water, and calves were monitored 1 wk postweaning. Average daily gain and body weight did not differ by treatment. Calves fed pSWM tended to have greater hip height (HH) than calves fed 80:20 (80.5 vs. 79.7 cm). Coconut oil tended to have a quadratic effect on HH, with calves fed 100:00, 80:20, and 60:40 at 79.2, 79.7, and 78.5 cm, respectively. No difference was observed in withers height between pSWM and 80:20. Coconut oil had a quadratic effect on withers height, with calves fed 100:00, 80:20, and 60:40 at 76.6, 77.5, and 76.5 cm, respectively. Change in HH from birth to 9 wk tended to be greater for calves fed pSWM than calves fed 80:20 (0.218 vs. 0.194 cm/d). Calves fed pSWM had higher milk dry matter intake (DMI) than calves fed 80:20 (0.580 vs. 0.518 kg/d). No effect of coconut oil was observed on milk DMI. Grain DMI and total DMI did not differ among treatments. Calves fed pSWM had an increase in days with a fecal score >2 compared with calves fed 80:20 (4.24 vs. 2.00 d). Coconut oil had a quadratic effect on fecal score, with calves fed 100:00, 80:20, and 60:40 scoring 4.00, 2.00, and 3.63 d, respectively. Respiratory score did not differ among treatments. In conclusion, DMI and average daily gain were similar among treatments. However, differences among treatments in skeletal growth and fecal scores are indicative of some possible benefits of medium-chain FA on calf health and performance.


Can mixed-species groups reduce individual parasite load? A field test with two closely related poeciliid fishes (Poecilia reticulata and Poecilia picta).
Predation and parasitism are two of the most important sources of mortality in nature. By forming groups, individuals can gain protection against predators but may increase their risk of being infected with contagious parasites. Animals might resolve this conflict by forming mixed-species groups thereby reducing the costs associated with parasites through a relative decrease in available hosts. We tested this hypothesis in a system with two closely related poeciliid fishes (Poecilia reticulata and Poecilia picta) and their host-specific monogenean ectoparasites (Gyrodactylus spp.) in Trinidad. Fish from three different rivers were sampled from single and mixed-species groups, measured and scanned for Gyrodactylus. The presence and abundance of Gyrodactylus were lower when fish of both species were part of mixed-species groups relative to single-species groups. This is consistent with the hypothesis that mixed-species groups provide a level of protection against contagious parasites. We discuss the importance of potentially confounding factors such as salinity and individual fish size.


[Comparative analysis of dynamics of health status indexes among school age children of Ukraine in modern conditions].
In the last time, there is a negative dynamics of indicators of the health of the child population in Ukraine in connection with socio-economic problems. The analysis of the data of the incidence and the prevalence of diseases among the children of the Poltava region in comparison with those of Ukraine for the period 2011-2015. In our work are used data of State statistics of incidence and prevalence of diseases among the child population of Ukraine. Analysis of the health status of children in the Poltava region and the country as a whole shows that due last 5 years there has been a destabilization of children's health - the incidence and prevalence of diseases, despite the positive trend, remain high. In the Poltava region for the period of 2011-2015 years there is a steady natural declining of the population (especially among rural residents), which is due to a decreasing in the birth rate and the increase in mortality. The incidence among children in rural areas of the Poltava region is 1000.8 per 1,000 children, which is lower than the average regional rate (1200.4) and significantly lower than the incidence of children in urban areas (1304.7).


MULTIPLE AUTHORSHIP TRENDS IN SCIENTIFIC PAPERS.
Since 1946 biomedical writers have shown no marked trend toward multiple authorship; the average number of authors per paper remains steady at about 2.3. This is in strong contrast tothe conclusion of Price from a study of Chemical Abstracts that the chemists' trend toward four or more authors per paper has been during this period, and continues to be, steeply exponential.


[Preparation and identification of rabbit polyclonal antibody against BCR-ABL b3a2 fusion protein].
Objective To prepare and identify rabbit anti-breakpoint cluster region-Abelson leukemia virus oncogene (BCR-ABL) b3a2 subtype polyclonal antibody. Methods A peptide containing the fusion sequence of the b3a2 subtype BCR-ABL fusion protein was designed and synthesized with the purity higher than 90%. The fusion polypeptide was coupled to Keyhole Limpet hemocyanin (KLH) and used to immune New Zealand rabbits. Antiserum was purified after multiple immunizations, in addition to using the b3a2 subtype fusion polypeptide for affinity purification. Peptides harboring only BCR or c-ABL amino acid sequences were also synthesized and used to purify the antibody in the secondary purification. The antibody that only bound to part of the epitope was absorbed and removed. ELISA and Western blotting were performed to determine the antibody titer and specificity. Results The rabbit serum background was low before immunization. The titer of the polyclonal antibody reached 1:32 000 after immunization, which met the experimental requirements. Western blotting showed that the antibody could specifically recognize the b3a2 subtype fusion protein of BCR-ABL. Conclusion The experiment has prepared the specific rabbit polyclonal antibody against BCR-ABL b3a2 subtype.


Photocurrent enhancement of BODIPY-based solution-processed small-molecule solar cells by dimerization via the meso position.
Three 4,4-difluoro-4-bora-3a,4a-diaza-s-indancene (BODIPY)-based small molecule donors H-T-BO, Br-T-BO, and DIMER were synthesized and fully characterized. Although modification at the meso position has a subtle influence on the light-harvesting ability, energy levels, and phase sizes, it has a striking effect on the packing behavior in solid film as two-dimension grazing incidence X-ray diffraction (2D GIXRD) and X-ray diffraction (XRD) confirm. Br-T-BO exhibits better packing ordering than H-T-BO in pristine film, which is beneficial from reinforced intermolecular interaction from halogen atoms. However, when [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) is blended, no diffraction patterns corresponding to the monomeric donor can be seen from the XRD data and both H-T-BO- and Br-T-BO-based blend films give a slightly blue-shifting absorption peak with respect to their neat ones, both of which imply destruction of the crystalline structure. As for DIMER, the enhancement of the intermolecular interaction arises not only from the expansion of the backbone but the "steric pairing effect" brought on by its twisted structure. When blended with PC71BM, the diffraction patterns of DIMER are, however, kept well and the absorption peak position remains unchanged, which indicates the ordered packing of DIMER is held well in blend film. In coincidence with the fact that packing ordering improves from H-T-BO to Br-T-BO and DIMER in pristine films and the ordered packing of DIMER even in blend film, DIMER-based devices show the highest and most balanced hole/electron mobility of 1.16 × 10(-3)/0.90 × 10(-3) cm(2) V(-1) s(-1)with respect to Br-T-BO (4.71 × 10(-4)/2.09 × 10(-4) cm(2) V(-1) s(-1)) and H-T-BO (4.27 × 10(-5)/1.00 × 10(-5) cm(2) V(-1) s(-1)) based ones. The short-circuit current density of the three molecule-based cells follows the same trend from H-T-BO (6.80) to Br-T-BO (7.62) and then to DIMER (11.28 mA cm(-2)). Finally, the H-T-BO-, Br-T-BO-, and DIMER-based optimal device exhibits a power conversion efficiency of 1.56%, 1.96%, and 3.13%, respectively.


Search for doubly charged Higgs boson production in multi-lepton final states with the ATLAS detector using proton-proton collisions at s = 13 TeV.
A search for doubly charged Higgs bosons with pairs of prompt, isolated, highly energetic leptons with the same electric charge is presented. The search uses a proton-proton collision data sample at a centre-of-mass energy of 13 TeV corresponding to 36.1 fb - 1 of integrated luminosity recorded in 2015 and 2016 by the ATLAS detector at the LHC. This analysis focuses on the decays H ± ± → e ± e ± , H ± ± → e ± μ ± and H ± ± → μ ± μ ± , fitting the dilepton mass spectra in several exclusive signal regions. No significant evidence of a signal is observed and corresponding limits on the production cross-section and consequently a lower limit on m ( H ± ± ) are derived at 95% confidence level. With ℓ ± ℓ ± = e ± e ± / μ ± μ ± / e ± μ ± , the observed lower limit on the mass of a doubly charged Higgs boson only coupling to left-handed leptons varies from 770 to 870 GeV (850 GeV expected) for B ( H ± ± → ℓ ± ℓ ± ) = 100 % and both the expected and observed mass limits are above 450 GeV for B ( H ± ± → ℓ ± ℓ ± ) = 10 % and any combination of partial branching ratios.


Immobilization of tyrosinase in carboxylic and carbonyl group-modified MWNT electrode and its application for sensing phenolics in red wines.
Tyrosinase-immobilized biosensor was fabricated based on PAAc-g-MWNT and PMAn-g-MWNT, respectively. The poly(acrylic acid)-grafted multi-wall carbon nanotubes, PAAc-g-MWNT, and poly(maleic anhydride)-grafted multi-wall carbon nanotube, PMAn-g-MWNT, were prepared by radiation-induced graft polymerization of acrylic acid (AAc) and maleic anhydride (MAn) on the surface of MWNT. The biosensor was prepared on ITO glass electrode by coating of chitosan solution with tyrosinase-immobilized PAAc-g-MWNT and PMAn-g-MWNT, respectively. The sensing ranges of the tyrosinase-immobilized biosensor based on PAAc-g-MWNT and PMAn were in the range of 0.2-0.9 mM concentration and in the range of 0.1-0.5 mM for phenol in phosphate buffer solution, respectively. Optimal pH and temperature conditions for sensing various phenolic compounds with tyrosinase-immobilized biosensor were determined. Total phenolic content for three commercial red wines on tyrosinase-immobilized biosensor were also determined.


How To Build a Successful Urgent-Start Peritoneal Dialysis Program.
In-center hemodialysis (HD) remains the predominant dialysis therapy in patients with ESKD. Many patients with ESKD present in late stage, requiring urgent dialysis initiation, and the majority start HD with central venous catheters (CVCs), which are associated with poor outcomes and high cost of care. Peritoneal dialysis (PD) catheters can be safely placed in such patients with late-presenting ESKD, obviating the need for CVCs. PD can begin almost immediately in the recumbent position, using low fill volumes. Such PD initiations, commencing within 2 weeks of the catheter placement, are termed urgent-start PD (USPD). Most patients with an intact peritoneal cavity and stable home situation are eligible for USPD. Although there is a small risk of PD catheter-related mechanical complications, most can be managed conservatively. Moreover, overall outcomes of USPD are comparable to those with planned PD initiations, in contrast to the high rate of catheter-related infections and bacteremia associated with urgent-start HD. The ongoing coronavirus disease 2019 pandemic has further exposed the vulnerability of patients with ESKD getting in-center HD. PD can mitigate the risk of infection by reducing environmental exposure to the virus. Thus, USPD is a safe and cost-effective option for unplanned dialysis initiation in patients with late-presenting ESKD. To develop a successful USPD program, a strong infrastructure with clear pathways is essential. Coordination of care between nephrologists, surgeons or interventionalists, and hospital and PD center staff is imperative so that patient education, home visits, PD catheter placements, and urgent PD initiations are accomplished expeditiously. Implementation of urgent-start PD will help to increase PD use, reduce cost, and improve patient outcomes, and will be a step forward in fostering the goal set by the Advancing American Kidney Health initiative.


Biased agonism at the parathyroid hormone receptor: a demonstration of functional selectivity in bone metabolism.
'Biased agonism' refers to the ability of a ligand to selectively recruit different intracellular signaling proteins to elicit distinct phenotypic effects in cells. While conventional G protein-coupled receptor (GPCR) agonism and antagonism can be regarded as modulating the quantity of efficacy, functionally selective or 'biased' ligands qualitatively change the trafficking of information flowing across the plasma membrane. The concept of ligand directed signaling fundamentally raises the potential of pharmacologic agents with novel therapeutic profiles possessing improved therapeutic efficacy or reduced side effects. Currently, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work examining biased agonism at the type I parathyroid hormone receptor (PTH1R) demonstrates that selective activation of G protein-independent arrestin-mediated signaling pathways elicits a physiologic response in bone distinct from that induced by the conventional PTH1R agonist PTH(1-34). While intermittent (daily) administration of PTH(1-34) (teriparitide) is effective in increasing bone formation, PTH(1-34) administration is also associated with increases in bone resorption and a propensity to promote hypercalcemia/hypercalcuria. In contrast, D-Trp12,Tyr34-bPTH(7-34) (PTH-βarr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. Unlike PTH(1-34), PTH-βarr appears to 'uncouple' the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands.


Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours.
Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features, such as oestrogen receptor (ER) status, grade and histological subtype. The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumour were analysed further for clinicopathological subgroups defined by ER status, grade and histological subtype. All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (P < 0.0001). The coefficient of variance (CV) between the spots was higher in ER-positive than in ER-negative cancers (72.6 versus 49.2%, P < 0.0001), and was highest in grade 3 (96.12%), grade 1 (87.27%) and invasive lobular tumours (83.59%) and lowest in medullary (26.48%) cancers. Nested analysis of variance indicated that in both ER-positive and ER-negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER-positive, 60% for ER-negative cancers) than the variance between tumours. Intratumoral heterogeneity in Ki67-LI is a ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision-making, and sheds new light on recommended cut-offs.


Characterization of Six Diamide Insecticides on Ryanodine Receptor: Resistance and Species Selectivity.
Ryanodine receptor (RyR) has been used as an insecticide target to control many destructive agricultural pests. The effectiveness of these insecticides has been limited by the spread of resistance mutations identified in pest RyRs, but the detailed molecular impacts of the individual mutations on the activity of different diamide compounds have not been fully explored. We created five HEK293 cell lines stably expressing wild type rabbit RyR1, wild type Spodoptera frugiperda RyR (Sf RyR), or Sf RyR carrying different resistance mutations, including G4891E, G4891E/I4734M, and Y4867F, respectively. R-CEPIA1er, a genetically encoded fluorescent protein, was also introduced in these cell lines to report the Ca2+ concentration in the endoplasmic reticulum. We systematically characterized the activities of six commercial diamide insecticides against different RyRs using the time-lapse fluorescence assay. Among them, cyantraniliprole (CYAN) displayed the highest activity against all three resistant Sf RyRs. The good performance of CYAN was confirmed by the toxicity assay using gene-edited Drosophila expressing the mutant RyRs, in which CYAN showed the lowest LD50 value for the double resistant mutant. In addition, we compared their acitivty between mammalian and insect RyRs and found that flubendiamide has the best insect-selectivity. The mechanism of the anti-resistance property and selectivity of the compounds was proposed based on the structural models generated by homology modeling and molecular docking. Our findings provide insights into the mechanism of insect resistance and guidance for developing effective RyR agonists that can selectively target resistant pests.


An entrepreneurial training model to enhance undergraduate training in biomedical research.
Undergraduate students who are interested in biomedical research typically work on a faculty member's research project, conduct one distinct task (e.g., running gels), and, step by step, enhance their skills. This "apprenticeship" model has been helpful in training many distinguished scientists over the years, but it has several potential drawbacks. For example, the students have limited autonomy, and may not understand the big picture, which may result in students giving up on their goals for a research career. Also, the model is costly and may greatly depend on a single mentor. The NIH Building Infrastructure Leading to Diversity (BUILD) Initiative has been established to fund innovative undergraduate research training programs and support institutional and faculty development of the recipient university. The training model at Morgan State University (MSU), namely "A Student-Centered Entrepreneurship Development training model" (ASCEND), is one of the 10 NIH BUILD-funded programs, and offers a novel, experimental "entrepreneurial" training approach. In the ASCEND training model, the students take the lead. They own the research, understand the big picture, and experience the entire scope of the research process, which we hypothesize will lead to a greater sense of self-efficacy and research competency, as well as an enhanced sense of science identity. They are also immersed in environments with substantial peer support, where they can exchange research ideas and share experiences. This is important for underrepresented minority students who might have fewer role models and less peer support in conducting research. In this article, we describe the MSU ASCEND entrepreneurial training model's components, rationale, and history, and how it may enhance undergraduate training in biomedical research that may be of benefit to other institutions. We also discuss evaluation methods, possible sustainability solutions, and programmatic challenges that can affect all types of science training interventions.