Mendelian randomization analysis to examine for a causal effect of urate on bone mineral density.
In observational studies, serum urate concentrations are positively associated with bone mineral density (BMD) and reduced risk of fragility fractures, raising the possibility that urate is a direct mediator of bone density. We used Mendelian randomization analysis to examine whether urate has a causal effect on BMD. We analyzed data from the Generation 3 cohort in the Framingham Heart Study (FHS) (N = 2501 total; 1265 male, 1236 female). A weighted genetic urate score was calculated using the SLC2A9, ABCG2, SLC17A1, SLC22A11, and SLC22A12 single-nucleotide polymorphisms (SNPs) that explains 3.4% of the variance in serum urate. Mendelian randomization analysis was performed using the two-stage least squares method with >80% power at α = 0.05 to detect an effect size equivalent to that observed in the ordinary least squares analysis between serum urate and total femur BMD. A strong association between serum urate and BMD was observed in the crude ordinary least squares analysis (total femur crude beta = 0.47, p = 1.7E-51). In the two-stage least squares analysis using the weighted genetic urate score as the instrumental variable, no significant relationship was observed between serum urate and BMD (total femur crude beta =-0.36, p = 0.06). Similar findings were observed in both the male and female subgroups, and there was no evidence for causality when individual SNPs were analyzed. Serum urate is strongly associated with BMD. However, controlling for confounders by Mendelian randomization analysis does not provide evidence that increased urate has a causal effect on increasing BMD.


Neurotensin receptor 1 facilitates intracellular and transepithelial delivery of macromolecules.
G protein-coupled receptors are expressed on the surface of eukaryotic cells and internalise in response to ligand binding. The actions of the hormone and neurotransmitter neurotensin (NT) are predominantly mediated by specific interactions with one such receptor, neurotensin receptor 1 (NTS1), which is upregulated in a variety of cancers, including pancreatic and breast tumours. NTS1 could therefore serve as a target for selective delivery of therapeutics. This study characterised the expression of NTS1 in HEK293 cells, as well as both polarised and non-polarised intestinal epithelial Caco-2 cells. NT-conjugated fluorophores were internalised in NTS1-expressing HEK293 and Caco-2 cells in a receptor-mediated fashion. Confocal microscopy revealed fluorophore localisation in the perinuclear region. Cell uptake and transport across the Caco-2 intestinal model of two NT-conjugated fluorophores (GFP and fluorescein) were compared to evaluate the effect of cargo size on cellular uptake. This work demonstrates that NT ligand conjugation is able to deliver relatively large macromolecular cargoes selectively into cells overexpressing NTS1 and the system is able to effectively translocate macromolecules across an intestinal epithelial model. NTS1 therefore shows potential as a drug delivery target not only for targeted but also non-invasive (oral) delivery of biotherapeutics for cancer.


Expansion of megakaryocyte progenitors from cryopreserved leukocyte concentrates of human placental and umbilical cord blood in short-term liquid culture.
Long-term severe thrombocytopenia following human placental and umbilical cord blood (CB) transplantation is a significant clinical problem. We studied the ex vivo expansion of megakaryocytic progenitor cells (CFU-Meg) from cryopreserved/thawed leukocyte concentrates (LC) of CB prepared by the Tokyo Cord Blood Bank protocol. The LC cells were cultured in serum-free culture medium supplemented with a combination of early-acting cytokines including thrombopoietin (TPO), flt3-ligand (FL), and stem cell factor (SCF). Combination of TPO plus FL, TPO plus SCF, and all of these cytokines together resulted in 8.9-, 7.7-, and 8.4-fold increases in CFU-Meg, respectively, by Day 5 of culture. Our results showed that this simple expansion strategy has the potential for expanding CFU-Meg from cryopreserved/thawed LC cells from CB.


Development of the neurotrophic keratopathy questionnaire: qualitative research.
Neurotrophic keratopathy/keratitis (NK) is a rare disease of the cornea that can lead to anatomical loss of the eye. Little is known about the NK experience from the patients' perspective. The objectives of this study were to examine the symptomatic experience and impacts of NK on patients and assess the overall comprehension, relevance, and content validity of a new questionnaire. This was a cross-sectional, qualitative study conducted with NK patients with varying levels of disease severity, recruited from one clinical site. One-on-one interviews using concept elicitation and cognitive interviewing techniques were conducted. Fourteen NK patients participated; 64.3% were female (n = 9), mean age was 65.7 ± 13.3, and 14.3% (n = 2), 21.4% (n = 3), and 64.3% (n = 9) were classified as Mackie stage I, stage II, or stage III, respectively. Participants reported 24 concepts, including: redness (n = 12, 86%), sensitivity to light (n = 11, 79%), general discomfort (n = 9, 64%), dry eye (n = 9, 64%), reduced visual acuity (n = 9, 64%), blurred vision (n = 8, 57%), and eye fatigue (n = 8, 57%). No new concepts were reported after the 13th interview. The most frequently reported impacts included frustration (n = 10, 71%), driving impairment (n = 8, 57%), reading impairment (n = 7, 50%), difficulty watching television (n = 7, 50%), and concern with potentially losing their eyesight due to NK (n = 6, 43%). Participants provided positive feedback on the draft NK Questionnaire (NKQ) and felt that it was comprehensive and relevant to their experience with NK. Additionally, the recall period, instructions, item concepts, and response options were well-understood by participants. Minor revisions were made to the tool for consistency (i.e., the timeframe "in the past 7 days" was added to items 12-14); item 14 was modified to include "how often"; examples were added to item 9. The results of the concept elicitation portion of the qualitative study support the content validity of the draft NKQ. The clinically significant concepts identified in the literature and raised during concept elicitation are included as items in the questionnaire. Further assessment of the psychometric properties should be conducted in support of this new tool to measure the effect of new treatments on symptoms and impacts associated with NK.


A systematic review of the measures that have been used to assess surface characteristics in relation to their impact on walking and falling.
We investigated whether an impediment to progress in understanding the environmental factors that cause falls may be the difficulty in comparing results across studies because walking surfaces are poorly defined and underspecified. We conducted a systematic review of 384 studies from 370 articles that tested how different surfaces influenced human walking and falling. For each study, we report which categories of surfaces were used (indoor, outdoor, treadmill, virtual reality and qualitative), the nature of each surface (stairs, slopes, slippery, compliant, rough or default) and how information about each surface was measured. We found that minimal information was provided for many surfaces, making it impossible to meaningfully compare results for different types of surfaces across studies. We conclude that most published studies of walking and falling provide insufficient data to describe the surfaces that they used and we provide recommendations about how to improve the reporting of walking surfaces.


Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA1 mRNA.
The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1, which is essential for viral genome maintenance but highly antigenic. EBV has seemingly evolved a system in which the mRNA sequence encoding the glycine-alanine repeats (GAr) of the EBNA1 protein limits its expression to the minimal level necessary for function while minimizing immune recognition. Here, we identify nucleolin (NCL) as a host factor required for this process via a direct interaction with G-quadruplexes formed in GAr-encoding mRNA sequence. Overexpression of NCL enhances GAr-based inhibition of EBNA1 protein expression, whereas its downregulation relieves the suppression of both expression and antigen presentation. Moreover, the G-quadruplex ligand PhenDC3 prevents NCL binding to EBNA1 mRNA and reverses GAr-mediated repression of EBNA1 expression and antigen presentation. Hence the NCL-EBNA1 mRNA interaction is a relevant therapeutic target to trigger an immune response against EBV-carrying cancers.


[A preliminary study on infection of rabbits by human cytomegalovirus AD169 strain].
To study the susceptibility of rabbit to human cytomeglavirus (HCMV) in vivo and in vitro. Rabbit embryo lung (REL) cell monolayer were inoculated with HCMV AD169 strain. The cytopathic effect (CPE) was observed by microscope. HCMV antigen was detected by immunohistochemical method and viral particles were shown by electron microscopy. Human embryo lung (HEL) was taken control. Thirty New Zealand rabbits were divided into three groups randomly, two were virus groups (group1, group2) and one was inactivated virus group (group3). 50 days later, the rabbits tissue lesions were observed by pathological techniques, HCMV DNA was analyzed by in situ hybridization. The CPE appeared 16 h post inoculation in REL cells as well as in HEL cells, at the same time, the HCMV antigen also was detected by immunhistochemistry and a large number of viral particles were manifested in the nucleus and cytoplasm of REL cells by electron microscope 36 h after virus inoculation. The extensive pathological damages in tissues of HCMV infected rabbits were observed and the viral DNA was also demonstrated in many tissues of HCMV infected rabbits. HCMV can infect REL cells and fulfil its replication cycle in vitro. HCMV AD169 strain can infect rabbits through intravenous injection and different infection models can be established by controlling the dosage of inoculated virus.


Psychotherapy in India: past, present, and future.
If psychotherapy is defined as "interpersonal method of mitigating suffering" then many psychotherapeutic systems have existed in India a long time. Unlike Western systems, these have lacked a clinical bias but have provided a more global framework. The future of psychotherapy in both East and West lies in discovering a conceptual framework with universal validity within which ad hoc therapies--for symptom relief, personality development, or interpersonal adjustment--can be developed.


Cost-effectiveness of active surveillance versus early surgery for thyroid micropapillary carcinoma based on diagnostic and treatment norms in China.
In this study, we compared the cost-effectiveness comparison of the active surveillance (AS) and early surgery (ES) approaches for papillary thyroid microcarcinoma (PTMC) from the perspective of the Chinese healthcare system. We performed a cost-effectiveness analysis using a Markov model of PTMC we developed to evaluate the incremental cost-effectiveness ratio of AS and ES. Our reference case was of a 40-year-old woman diagnosed with unifocal (<10 mm) PTMC. Relevant data were extracted after an extensive literature review, and the cost incurred in each state was determined using China Medicare data on payments for ES and AS. The willingness-to-pay threshold was set at ¥242,928/quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to account for any uncertainty in the model's variables. Additional subgroup analyses were performed to determine whether AS was cost-effective when different initial monitoring ages were used. ES exhibited an effectiveness of 5.2 QALYs, whereas AS showed an effectiveness of 25.8 QALYs. Furthermore, the incremental cost-effectiveness ratio for ES versus AS was ¥1,009/QALY. The findings of all sensitivity analyses were robust. Compared with ES, AS was found to be the cost-effective strategy at initial monitoring ages of 20 and 60 years, with an incremental cost-effectiveness ratio of ¥3,431/QALY and -¥1,316/QALY at 20 and 60 years, respectively. AS was a more cost-effective strategy in patients with PTMC aged more than 60. With respect to the norms of the Chinese healthcare system, AS was more cost-effective for PTMC over lifetime surveillance than ES. Furthermore, it was cost-effective even when the initial monitoring ages were different. In addition, if AS is incorporated into the management plan for PTMC in China at the earliest possible stage, a predicted savings of ¥10 × 108/year could be enabled for every 50,000 cases of PTMC, which indicates a good economic return for future management programs. The identification of such nuances can help physicians and patients determine the best and most individualized long-term management strategy for low-risk PTMC.


Intraocular pressure following aphakic transplants.
Timolol maleate produced no significant difference in the initial mean intraocular pressure after keratoplasty using disparate-sized grafts (7.5 mm recipient, 8.0 mm donor). However, timolol did significantly reduce the number of eyes with an intraocular pressure elevation greater than 24 mm Hg. A series of patients with equal-sized donor and recipient cuts (8.0 mm) had initial intraocular pressure of 19.6 mm Hg. The normal intraocular pressure in these patients is thought to be due to superficial suturing, thereby preventing angle distortion.


Processive nature of reverse transcription by avian myeloblastosis virus deoxyribonucleic acid polymerase.
The ribonucleic acid dependent deoxyribonucleic acid polymerase from avian myeloblastosis virus was shown to synthesize poly(dT) transcripts by a processive mechanism using poly(rA)1100.oligo(dT)12-18 as template and primer. Template challenge experiments demonstrate that at low temperature and ionic strength, the polymerase remains bound to the completed template-daughter strand complex after completion of daughter strand elongation. Higher temperatures and ionic strength increase the dissociation of the enzyme from the complex, thus reducing transcript length. Analysis of product size and quantity indicates that the degree of processivity is also influenced by the types and concentrations of metal ions present and indicates that the metal ions affect the activity of the poly(rA) as a template more than they affect processivity or enzyme activity. The results also lead to the conclusion that initiation is the rate-limiting step under all of our experimental conditions. The arguments for a processive as opposed to distributive mechanism are based on an analysis of enzyme-template interactions, product size, and amount of product made under specific reaction conditions.


The validity and reliability of the Turkish version of short-form McGill Pain Questionnaire in patients with leukemia.
To assess reliability and validity of the Turkish version of the Short-form McGill Pain Questionnaire. Pain is one of the most frequent and significant problems encountered by nurses practice across the world. The Short-form McGill Pain Questionnaire was widely translated and used to assess the pain experience of several types of patients because it combines the properties of the standard McGill Pain Questionnaire but takes substantially less time to administer. The study used psychometric testing to establish reliability and validity of the Turkish version of Short-form McGill Pain Questionnaire. A convenience sample of 160 patients with leukaemia in Turkey was used to collect data regarding pain evaluation. The original version of the Short-form McGill Pain Questionnaire, adapted into Turkish, was tested for internal consistency, content validity, construct validity and concurrent validity. Internal consistency was found adequate at both assessments with Cronbach's α 0.88 for test and 0.91 for retest. For reliability of the total, sensory, affective and evaluative total pain intensity, high intraclass correlations were demonstrated (0.85, 0.84, 0.82 and 0.70, respectively). Correlation of total, sensory and affective score with the numerical rating scale was tested for construct validity demonstrating r = 0.61 (p < 0.01) for test and r = 0.68 (p < 0.01) for retest. Correlation with blood pressure values for concurrent validity was found to be r = 0.78 (p < 0.001) for test and r = 0.73 (p < 0.001) for retest. Turkish version of the Short-form McGill Pain Questionnaire has shown statistically acceptable levels of reliability and validity for pain evaluation in patients with leukaemia. This study provided evidence that the Turkish version of the Short-form McGill Pain Questionnaire is a reliable and valid instrument for assessing pain. This scale can be used to assess nursing interventions aimed at decreasing pain and efficacy of the treatment.


A new inflammatory marker in overweight patients: triggering receptor expressed on myeloid cells-1.
Triggering receptor expressed on myeloid cells 1 (TREM-1) is secreted by phagocytes in adipose tissue and it also upregulates the expression of genes involved in the inflammatory response and atherosclerotic conditions. This study was aimed to investigate the serum TREM-1 levels in overweight patients. Twenty-eight subjects in the overweight group (OG) and 20 age-matched healthy subjects in the control group (CG) (BMI 27.6±1.2 vs 23.1±2.17 kg/m2, respectively, p<0.001) were included in the study. The serum sTREM-1 level was measured by ELISA. The homeostasis model assessment score (HOMA-IR) was also calculated. The mean TREM-1 levels were significantly higher in OG than in CG (407.3±323.7 vs 150.3±152.7 pg/mL, respectively, p<0.001). The HOMA-IR score was also significantly higher in OG than in CG (3.42±3.63 vs 2.77±1.61, respectively). A positive correlation was detected between TREM-1 and BMI (r=0.318, p=0.028). This study mainly demonstrated that a high serum TREM-1 level might be an early inflammatory marker in overweight patients. We found that TREM-1 might be associated with BMI in overweight patients regardless of insulin resistance (Tab. 1, Ref. 21). Text in PDF www.elis.sk.


Commonly dysregulated genes in murine APL cells.
To identify genes that are commonly dysregulated in a murine model of acute promyelocytic leukemia (APL), we first defined gene expression patterns during normal murine myeloid development; serial gene expression profiling studies were performed with primary murine hematopoietic progenitors that were induced to undergo myeloid maturation in vitro with G-CSF. Many genes were reproducibly expressed in restricted developmental "windows," suggesting a structured hierarchy of expression that is relevant for the induction of developmental fates and/or differentiated cell functions. We compared the normal myeloid developmental transcriptome with that of APL cells derived from mice expressing PML-RARalpha under control of the murine cathepsin G locus. While many promyelocyte-specific genes were highly expressed in all APL samples, 116 genes were reproducibly dysregulated in many independent APL samples, including Fos, Jun, Egr1, Tnf, and Vcam1. However, this set of commonly dysregulated genes was expressed normally in preleukemic, early myeloid cells from the same mouse model, suggesting that dysregulation occurs as a "downstream" event during disease progression. These studies suggest that the genetic events that lead to APL progression may converge on common pathways that are important for leukemia pathogenesis.


Treating peripheral arterial disease in patients with diabetes.
Diabetes is associated with considerably higher risks of developing peripheral arterial disease (PAD) which, when it occurs, is more severe and progresses more rapidly than in nondiabetics. Early detection of PAD in the diabetic patient is therefore important, but may be complicated by the presence of neuropathy and calcification of the arteries such that ischaemic symptoms are not felt by the patient and ankle pressures are not reduced. Toe pressures are an alternative diagnostic tool in these patients. Good glycaemic control, while an essential part of diabetes management, does not appear to bring more than modest benefits in preventing the peripheral vascular complications of diabetes. Therefore, attention to other risk factors is needed. Treatment with the phosphodiesterase III inhibitor, cilostazol, has been shown to improve walking distances significantly in diabetes patients with intermittent claudication and also appears to improve plasma lipid profiles. Further, cilostazol has an antiplatelet action, which may prove to be of benefit in diabetes because hyperglycaemia is associated with increased platelet aggregability. Revascularization in diabetes patients with critical leg ischaemia is complex and associated with poorer outcomes than in non-diabetes patients. While surgical revascularization has better patency rates, in patients at high risk of surgical complications, percutaneous transluminal angioplasty may be a better option.


The effects of gas flaring as moderated by government quality in leading natural gas flaring economies.
This study seeks to address pertinent economic and environmental issues associated with natural gas flaring, especially for the world's leading natural gas flaring economies (i.e. Russia, Iraq, Iran, the United States, Algeria, Venezuela, and Nigeria). By applying relevant empirical panel and country-specific approaches, the study found that fuel energy export positively impacts economic growth with elasticity of ~ 0.22 to ~ 0.24 for the panel examination. It is further revealed that environmental quality in the panel is hampered by increase in economic growth, gas flaring, fuel energy export, and urbanization. Moreover, for the country-wise inference, government quality desirably moderates economic and environmental aspects of gas flaring in Venezuela and Nigeria, and in Russia and Iran respectively. However, government quality moderates gas flaring to cause economic downturn in the USA. Additionally, economic growth increased with increase in urbanisation (in Iraq and the USA), gas flaring (in Iran and the USA), government quality (only in the USA), and fuel energy export (only in Algeria) while economic growth downturn is due to increase urbanisation in Russia and the USA, increase in fuel energy export in the USA, and increase in government quality in Russia. Meanwhile, environmental quality is worsened through intense carbon dioxide emission from increased urbanisation activity (in Iraq, Iran, Algeria, and Nigeria), increased fuel energy export (in Nigeria), increased natural gas flaring (in Algeria and Nigeria), increased GDP (in Russia, Iran, USA, Algeria, and Venezuela), and high government quality (in Iran). Interestingly, the result revealed that increase in GDP (in Nigeria), increase in urbanisation (in the USA), and increase in gas flaring (in Algeria and Nigeria) dampens environmental quality. Importantly, this study offers policy insight into sustainable approaches in natural gas production, government effectiveness, and regulatory quality.


Voices: A Conversation with Allen J. Wilcox.
Allen James Wilcox was born on 30 September 1946 in Columbus, OH. He studied medicine at the University of Michigan, graduated in 1973, and after a rotating internship, he completed a master's degree in maternal and child health (1976) and a PhD in epidemiology (1979) at the University of North Carolina in Chapel Hill. After graduation, he went to work at the National Institute of Environmental Health Sciences (NIEHS, one of the US National Institutes of Health) in Durham, NC, where he has spent his career. He developed a research program in reproductive and perinatal epidemiology, a relatively unexplored area at the time. His studies include the early pregnancy study, which documented the extent of subclinical pregnancy loss in humans and established the fertile days of a woman's menstrual cycle. He served as the Chief of the Epidemiology Branch from 1991 to 2001, and as Editor-in-Chief of the journal EPIDEMIOLOGY from 2001 to 2014. His textbook, Fertility and Pregnancy-An Epidemiologic Perspective, was published by Oxford University Press in 2010. He was elected to the American Epidemiological Society in 1989, and served as its president in 2003. He also served as president of the Society of Pediatric and Perinatal Epidemiological Research (1996) and the president of the Society of Epidemiological Research (1998). He holds adjunct teaching appointments at the University of North Carolina, Harvard University, and the University of Bergen (Norway), which awarded him an honorary doctoral degree in 2008.


Decreased urinary peptide excretion in patients with renal disease.
Normal urine contains low-molecular-weight peptides or protein fragments that have been poorly studied, primarily because of the technical difficulty of measuring peptides in the presence of proteins. We studied these substances in healthy subjects and patients with renal disease and varying degrees of proteinuria to understand the factors that determine their excretion. We estimated these substances as the difference between results using the Lowry method (which detects both proteins and peptides) and those obtained using the dye-binding Bradford (Biorad) method (Biorad Laboratories Inc, Hercules, CA; which detects only proteins). We validated this 2-assay approach to measure peptide levels by showing that such proteins as immunoglobulin G, albumin, and lysozyme were measured equally by the Lowry and Biorad methods, whereas degraded proteins were recognized by the Lowry method only, but not by the Biorad method. We found that healthy subjects excreted less than 200 mg of protein, but 3 to 4 g of peptides/g creatinine; thus, peptides constituted approximately 95% of total protein material excreted in urine. Patients with renal disease and proteinuria had a progressive decrease in peptide excretion, ranging from 3 to 0 g/g creatinine. Twenty-five percent of nephrotic patients (18 of 72 patients) excreted very small amounts of peptides in urine (0% to 10% of total protein material). We found that healthy persons excrete substantial amounts of peptides in urine, and this excretion decreases in the presence of proteinuric renal disease. It is possible that these peptides in urine arise from the tubular degradation of filtered proteins and exocytosis of protein fragments toward the urinary side, a process that becomes increasingly impaired as proteinuria increases.


The application of electro- and magneto-encephalography in tinnitus research - methods and interpretations.
In recent years, there has been a significant increase in the use of electroencephalography (EEG) and magnetoencephalography (MEG) to investigate changes in oscillatory brain activity associated with tinnitus with many conflicting results. Current view of the underlying mechanism of tinnitus is that it results from changes in brain activity in various structures of the brain as a consequence of sensory deprivation. This in turn gives rise to increased spontaneous activity and/or synchrony in the auditory centers but also involves modulation from non-auditory processes from structures of the limbic and paralimbic system. Some of the neural changes associated with tinnitus may be assessed non-invasively in human beings with MEG and EEG (M/EEG) in ways, which are superior to animal studies and other non-invasive imaging techniques. However, both MEG and EEG have their limitations and research results can be misinterpreted without appropriate consideration of these limitations. In this article, I intend to provide a brief review of these techniques, describe what the recorded signals reflect in terms of the underlying neural activity, and their strengths and limitations. I also discuss some pertinent methodological issues involved in tinnitus-related studies and conclude with suggestions to minimize possible discrepancies between results. The overall message is that while MEG and EEG are extremely useful techniques, the interpretation of results from tinnitus studies requires much caution given the individual variability in oscillatory activity and the limits of these techniques.


Use of PMMA in expansion dental implants.
The Polymer Expansion Implant System, which is a system for the substitution of missing dental roots in natural or surgical alveolus, has been developed by the author. The polymer used is poly (methyl methacrylate) (PMMA). A material is sought that has three of the basic physical and mechanical qualities of human dentine: low modulus of elasticity, thermal and electrical passiveness, and ideal porosity. In addition it should be resistant, easily worked, biocompatible, and of low cost. Of the biomedical polymers, PMMA has these qualities, and it can be used as a substitute for dental roots. The design of bodies to be implanted as substitutes for dental roots requires: anatomical measurements of the maxilla and sockets; methods of retention by the bone tissue; and methods of insertion. The formation of lamina dura around an implanted body is a reply of the organism to the forces acting on it and a demonstration of the good interaction of the porosity of the material, the peri-implant collagenous fibers and bone. X-rays that demonstrate the behavior of bone to a PMMA implant are shown.


Cost-utility analysis of magnetoencephalography used to inform intracranial electrode placement in patients with drug resistant epilepsy: a model based analysis.
We estimated the cost-effectiveness of adding magnetoencephalography to a standard assessment for epilepsy surgery consisting of neuropsychology, magnetic resonance imagining, scalp electroencephalography, video electroencephalography and intracranial electroencephalography, in the capacity of informing intracranial electroencephalography electrode placement. We used Microsoft Excel (2007) to construct a decision model. Discounted costs and quality adjusted life years are aggregated to calculate incremental cost-effectiveness ratios. Sensitivity analyses are conducted to assess robustness of findings. Our base case analysis yielded a result of $14 300 per quality adjusted life year gained. A total of 82.7% of probabilistic sensitivity analysis iterations resulted in incremental cost-effectiveness ratios below $100 000 in 2014 Canadian dollars. Our findings demonstrate that the inclusion of Magnetoencephalography in the assessment for epilepsy surgery in the capacity of informing intracranial electroencephalography electrode placement is likely not cost saving but does represent a reasonable allocation of resources from a value for money perspective.


An insight into the hydrogen bonding, halogen bonding and chalcogen bonding interactions in manganese(iii) complexes with N2O2donor salicylidine Schiff base ligands.
Four manganese(iii) complexes, [MnL1(H2O)2]ClO4·H2O (1), [MnL2(H2O)2]ClO4 (2), [MnL3(DMSO)(H2O)]ClO4 (3) and [MnL4(DMSO)(H2O)]ClO4 (4), where H2L1 = N,N'-bis(5-bromosalicylidene)-1,3-diaminopropane, H2L2 = 2,2-dimethyl-N,N-bis(3-methyloxysalicylidene)-1,3-diaminopropane, H2L3 = N,N'-bis(5-chlorosalicylidene)-2,2-dimethyl-1,3-diaminopropane and H2L4 = 2-hydroxy-N,N'-bis(3-ethyloxysalicylidene)-1,3-diaminopropane are tetradentate N2O2-donor ligands and DMSO = dimethyl sulfoxide, have been synthesized and characterised by elemental analysis, IR and UV-vis spectroscopy and single-crystal X-ray diffraction studies. All are monomeric complexes. Complex 1 crystallises in orthorhombic space group P212121, complex 3 crystallises in triclinic space group P-1, whereas complexes 2 and 4 crystallize in monoclinic space groups, C2/c and C2/m respectively. In all the complexes, manganese(iii) has a six-coordinated pseudo-octahedral geometry in which imine nitrogen atoms and phenolate oxygen atoms of the deprotonated di-Schiff base constitute the equatorial plane. In complexes 1 and 2, water molecules are present in the fifth and sixth coordination sites in the axial positions while in complexes 3 and 4 they are occupied by one water and one DMSO. The coordinated water molecules initiate hydrogen-bonded networks in all complexes. DFT calculations have been carried out to analyze two aspects of these complexes viz. the formation of halogen (HaB) and chalcogen bonding (ChB) interactions in complexes 1 and 3 where the electron donor is the perchlorate anion and the acceptor either bromine or chlorine atoms for the HaBs and the sulfur atom of the coordinated DMSO for the ChB. In addition, other intermolecular effects are discussed in the solid state for complexes 1, 2 and 4, where the hydrogen atoms of the coordinated water molecules interact with the electron rich cavities formed by the phenolate and alkyloxy oxygen atoms of the Schiff-base ligand.


Simultaneous Occurrence of Guillain-Barré Syndrome in Three Members of the Same Family: A Case Report.
Guillain-Barré syndrome (GBS) is an autoimmune demyelinating disease that is usually triggered by an antecedent infection and is characterized by flaccid paralysis and hyporeflexia. Although a sporadic disease, a few cases of GBS have been reported in families, suggesting a genetic predisposition. Here, we present a case of simultaneous occurrence of GBS in three members of the same family, with two members having a preceding history of diarrhea. They were diagnosed via cerebrospinal fluid routine examination and nerve conduction study and responded to plasmapheresis. This suggests possible genetic susceptibility along with environmental triggers in the pathogenesis of GBS.


Improvements in the equation for calculating the contribution to osmotic potential of the separate solutes of water solutions.
A minor conceptual improvement, the elimination of an approximation and its revision in relativistic terms, has resulted in a twofold increase in the predictability of the equation for calculating the contribution to osmotic potential of the separate solutes of water solutions. The molecular model inherent to its formulation would provide unifying principles for visualizing water movements associated with solute concentration gradients in tissues.


Enhanced adsorption of diclofenac onto activated carbon derived from PET plastic by one-step pyrolysis with KOH.
Plastic pollution is a severe threat to the health of ecosystems, and recycling plastics is recognized as a key control strategy. This study used the one-step pyrolysis assisted with KOH activation to recycle the widely used polyethylene terephthalate (PET) plastic as activated carbon (PET-AC) which was subsequently applied to adsorb diclofenac (DCF), a frequently detected emerging contaminant in water, for the first time. It was found that both the pyrolysis temperature and the addition of KOH can effectively regulate the pore sizes and volumes of PET-AC. PET-AC obtained at 700 °C demonstrated a high adsorption capacity of DCF up to 179.42 mg g-1 at 45 °C. The adsorption kinetics was conducted with both static jar and dynamic column tests and analyzed with various models. Thermodynamic results demonstrated that the adsorption of DCF was spontaneous and endothermic. The material also presented an excellent potential to adsorb other pharmaceuticals and personal care products in water. XPS and FTIR analysis indicated that the adsorption might be mainly driven by the physical forces, especially π-π interaction and hydrogen bonding. This study provided a reference for recycling waste plastic as an efficient adsorbent to eliminate organic contaminants from water.


MiR-15a expression analysis in non-small cell lung cancer A549 cells under local hypoxia microenvironment.
Lung cancer is a common tumor in the clinic. Hypoxia is an important biological characteristic in the solid malignant tumor. MiRNA participates in cell proliferation, differentiation, and apoptosis. This study tested hypoxia-inducible factor 1-α (HIF-1α) in lung cancer patients and analyzed the microRNA-15a (miR-15a) expression in A549 cells under different local hypoxia microenvironments. A total of 40 non-small cell lung cancer (NSCLC) patients in First Affiliated Hospital of Zhengzhou University between Jan 2015 and Jan 2016 were involved in this study. The serum and tissue samples of lung cancer were collected. Serum HIF-1α level was tested by enzyme-linked immunosorbent assay (ELISA) assay. HIF-1α expression in tissue was evaluated by using the immunohistochemistry. A549 cells were cultured under normoxic, hypoxic, and anaerobic environment, respectively. HIF-1α mRNA and miR-15a levels were determined by RT-PCR. HIF-1α levels were up-regulated in serum and tissue (p<0.05). HIF-1α mRNA increased, while miR-15a down-regulated in A549 from hypoxia and anaerobic groups compared with control (p<0.05). HIF-1α shRNA transfection significantly reduced HIF-1α and elevated miR-15a level (p<0.05). MiR-15a shRNA transfection exhibited no statistical impact on HIF-1α expression (p>0.05). HIF-1α highly expressed in lung cancer patients. MiR-15a levels were down-regulated in A549 cells under hypoxia and anaerobic conditions.


The role of spore morphology in horizontal transmission of a microsporidium of Daphnia.
The microsporidian parasite Hamiltosporidium tvaerminnensis can infect Daphnia magna both horizontally (through environmental spores) and vertically (through parthenogenetic and sexually produced eggs). The spores of H. tvaerminnensis come in three distinguishable morphologies, which are thought to have different roles in the transmission of the parasite. In this study, we examined the role of the two most common spore morphologies (i.e. oval-shaped spores and pear-shaped spores) in horizontal transmission of H. tvaerminnensis. To this end, we infected hosts with solutions consisting of either mostly oval- or mostly pear-shaped spores, and quantified infection rates, parasite-induced host mortality and mean number of parasite spores produced per host. We found that spore morphology by itself did not influence infection rates and parasite-induced host mortality. Instead, host clone and parasite isolate interacted with spore morphology in shaping infection outcome and mortality. Thus, there appear to be strong genotype-by-genotype (G × G) interactions in this system. While there is no dispute that H. tvaerminnensis can transmit both vertically and horizontally, our findings do not support theoretical predictions that different spore morphologies hold different roles in horizontal transmission of H. tvaerminnensis.


Variability of peak speed and sprinting actions during the same small-sided games: within- and between-player variations inspected over four consecutive weeks.
This study aimed to analyze within- and between-player variations of peak speed and sprinting actions occurring in small-sided games (SSGs: 1 v 1 and 5 v 5). The study followed a cohort study design. Twenty male youth soccer players (age: 17 years old) from the same team were observed over four consecutive weeks. Each week, the players participated in two sessions (day one and day two) during which SSGs were applied. The 1 vs. 1 format was employed with four repetitions of thirty seconds interspaced with two-minute rest intervals, while the 5 vs. 5 format with four repetitions of four minutes and two-minute rest intervals between them. The players were monitored during all training sessions with the Polar Team Pro. The peak speed attained in each game, and the number of sprints were extracted as the primary outcomes. The between-player variability revealed a lower coefficient of variations for peak speed in the 1 vs. 1 (13.9%) and 5 vs. 5 (10.9%) formats than for sprints (1 v 1: 64.7%; 5 v 5: 65.5%). Considering the within-player variability, it was observed that sprints were more variable (1 vs. 1: 62.1%; 5 v 5: 65.7%) than peak speed (1 vs. 1: 16.4%; 5 v 5: 14.0%). The between-session analysis revealed that during week 1 (day 1), peak speed was significantly higher than during week 3 (day 1) in the 1 vs. 1 format (+3.0 km/h; p = 0.031; d = 1.296). Moreover, peak speed during week 3 (day 2) was considerably lower than during week 1 (-5.9 km/h; p < 0.001; d = 1.686) and week 2 (-5.0 km/h; p = 0.001; d = 1.639). The between-session analysis showed no significant differences in the sprint between the sessions on day 1 (p > 0.05). However, on day two, the sprint was substantially higher during week one than during week four in the 5 vs. 5 format (+5.40 n; p = 0.002; d = 2.571). In conclusion, this study revealed that peak speed presents lower within- and between-player variability than the number of sprints. Considering these two measures, there are no considerable variations between the weeks. Coaches should consider identifying strategies to stabilize the stimulus regarding the number of sprints if this represents one of the targets for employing SSGs.


The biology, structure, and function of eyebrow hair.
Eyebrow hair serves many important biologic and aesthetic functions. This article reviews the structure and function of the hair follicle, as well as hair follicle morphogenesis and cycling. Eyebrow hair follicles share the same basic structure as hair follicles elsewhere on the body, but are distinguished by their shorter anagen (growing) phase. Knowledge of the hair follicle structure and cycle is important for understanding the pathophysiology of alopecia, as diseases affecting the stem cell portion of the hair follicle in the bulge region may cause permanent hair loss. Furthermore, therapeutic agents that target distinct phases and hormones involved in the hair cycle may be useful for promoting hair growth.


Rib fractures in the elderly: physiology trumps anatomy.
Rib fractures in elderly patients are associated with increased morbidity and mortality. Predicting which patients are at risk for complications is an area of debate. Current models use anatomic, physiologic or laboratory parameters in isolation to answer this question. The 'RibScore' is an anatomic model that assesses fracture severity. Given that frailty is a major driver of adverse outcomes in the elderly, we hypothesize that the combined analysis of fracture severity, physiologic reserve and current pulmonary function are better predictors of respiratory compromise in this population. This is a retrospective chart review of 263 trauma patients age ≥55 from January 2014 to June 2017. Criteria included blunt mechanism and ≥ 1 rib fracture identified by CT. Variables indicating adverse pulmonary outcomes were defined by: pneumonia, respiratory failure and tracheostomy. Three models were assessed: (1) RibScore, (2) Modified Frailty Index (mFI) and (3) initial partial pressure of carbondioxide (PaCO2). A total of 263 patients met inclusion criteria. 13% developed pulmonary complications. Increased RibScore, mFI and PaCO2 were each statistically associated with risk of complications. Receiver operating characteristics area under the curve analysis of individual models predicted complications with the following concordance statistic (CS): anatomic (RibScore) yielded a CS of 0.79 (95% CI 0.69 to 0.89); physiologic (mFI) yielded a CS of 0.83 (95% CI 0.75 to 0.91) and laboratory (PaCO2) yielded a CS of 0.88 (95% CI 0.80 to 0.95). The PaCO2 had the highest discriminative ability of the three individual models. Combining all three models yielded the best performance with a CS of 0.90 (95% CI 0.81 to 0.97). The RibScore maintains discriminative ability in the elderly. However, models based on mFI and PaCO2 individually outperform the RibScore. A combination of all three models yields the highest discriminative ability. This combined approach is best for assessing the severity of rib fractures and prediction of complications in the elderly. Prognostic Study, Level III.


[Problems of the preservation treatment of vesical function of bladder cancer].
Prognosis of the recurrent cases which broke out after the preservation treatment of the vesical function as a first treatment tend to be worse in comparison with the primary cases. Especially the partial cystectomy has this tendency. Preservation treatment of the vesical function can be applied to the low stage, however, the application of this treatment to the tumor which is indicative of the invasive cancer is very difficult. From the long term observation type 1 (bush type) by the endoscopic classification did not worsen in a recurrence after the treatment with preservation of the vesical function. A repetition of the preservation treatment of the vesical function for a intravesical recurrence will incur a danger that a tumor will be getting worse even if it is low grade or low stage.


Twist-1 regulates the miR-199a/214 cluster during development.
MicroRNAs are known to regulate developmental processes but their mechanism of regulation remains largely uncharacterized. We show the transcription factor Twist-1 drives the expression of a 7.9-kb noncoding RNA transcript (from the Dynamin-3 gene intron) that encodes a miR-199a and miR-214 cluster. We also show that knocking down Twist-1 with shRNAs decreased miR-199a/214 levels and that Twist-1 bound an E-Box promoter motif to developmentally regulate the expression of these miRNAs. The expression of HIF-1 (known to mediate Twist-1 transcription), miR-199a and miR-214 was maximal at E12.5 and the miRNAs were expressed specifically in mouse cerebellum, midbrain, nasal process and fore- and hindlimb buds. This study shows the expression of the miR199a/214 cluster is controlled by Twist-1 via an E-Box promoter element and supports a role for these miRNAs as novel intermediates in the pathways controlling the development of specific neural cell populations.


Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future.
Breast cancer is the most common cancer among women in the United States, with up to 30% of those diagnosed displaying a family history of breast cancer. To date, 18% of the familial risk of breast cancer can be explained by SNPs. This review summarizes the discovery of risk-associated SNPs using candidate gene and genome-wide association studies (GWAS), including discovery and replication in large collaborative efforts such as The Collaborative Oncologic Gene-environment Study and OncoArray. We discuss the evolution of GWAS studies, efforts to discover additional SNPs, and methods for identifying causal variants. We summarize findings associated with overall breast cancer, pathologic subtypes, and mutation carriers (BRCA1, BRCA2, and CHEK2). In addition, we summarize the development of polygenic risk scores (PRS) using the risk-associated SNPs and show how PRS can contribute to estimation of individual risks for developing breast cancer. Cancer Epidemiol Biomarkers Prev; 27(4); 380-94. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."


[Course of pregnancy and labor following cytostatic treatment of trophoblastic tumors].
In our department 24 patients underwent treatment of invasive trophoblastic tumours from 1975 to 1984. In 13 cases we were dealing with invasive bladder moles and in 11 cases with chorionic carcinoma. Nine women became pregnant, among them one case of chorionic carcinoma. Eight women were delivered of a viable child on average 30 months after the end of the treatment, whereas one patient wanted termination of pregnancy. Six women had undergone a methotrexate monotherapy before, two women a sequential treatment with methotrexate + actinomycine D. The undisturbed pregnancies and births of eight healthy babies point to an unimpaired fertility after chemotherapy of trophoblastic tumours.


Would your judgment stand up to scrutiny?
This article examines the process of decision making in nurses' professional practice. It outlines different aids that may be used to assist nurses in making decisions that influence patient care. It also asks nurses to consider whether their decision-making processes are sound, scientific and open to external examination.


Contact Toxicity of Deltamethrin Against Tribolium castaneum (Coleoptera: Tenebrionidae), Sitophilus oryzae (Coleoptera: Curculionidae), and Rhyzopertha dominica (Coleoptera: Bostrichidae) Adults.
This study was conducted at Oklahoma State University, Stillwater, OK, to evaluate the response to deltamethrin concentrations for adults of three stored-product insects, Tribolium castaneum (Herbst), Sitophilus oryzae (L.), and Rhyzopertha dominica (F.). In insect toxicological studies, knockdown is the state of intoxication and partial paralysis as a result of exposure to an insecticide. Deltamethrin concentrations ranging from 0.48 to 140 mg/m(2) (1 to 3,000 ppm) were sprayed on glass Petri dishes. After the dishes dried, 20 adult insects of each species were placed on the treated dishes to determine the contact toxicity of deltamethrin. Assessments for knockdown were made at 15-min intervals for up to 8 h after initial exposure and then again after 24 or 48 h. Insects were then transferred to clean untreated Petri dishes with diet and observed from 0.5 to 72 h. Mortality was assessed 72 h after transfer to untreated dishes with food material. Deltamethrin was highly effective against all three species tested and achieved 99% knockdown of insects of all species within 4 h after exposure at concentrations ≥1.2 mg/m(2) Although some insects recovered from initial knockdown at concentrations ≤48 mg/m(2), nearly all the insects were killed at 140 mg/m(2) when exposed for 48 h. LC95 values for all species tested, for the 48-h exposure period, were <140 mg/m(2), the concentration of deltamethrin that could potentially be present in new ZeroFly Storage Bag fabric. ZeroFly bags are used for stored-product insect pest control.


Immunization with interleukin-2-secreting allogeneic cells transfected with DNA from mouse melanoma cells induces immune responses that prolong the lives of mice with melanoma.
Altered genes in tumor cells specify tumor-associated antigens. Because genetic instability is a characteristic of the malignant cell phenotype, a large number of different, altered genes may be present in a population of neoplastic cells, specifying an array of undefined tumor-associated determinants. We hypothesized that immunogenic cells transfected with DNA from malignant cells will include cells that specify tumor-associated antigens. To test this question, we deliberately mutagenized a population of B16 melanoma cells (H-2b) by ultraviolet-B irradiation. DNA from the surviving cells was used to transfect LM cells (H-2k), a mouse fibroblast cell line modified previously to secrete interleukin-2. The transfected allogeneic cells were then tested for their immunogenic properties in C57BL/6J mice (H-2b) syngeneic with the melanoma. Mice injected with a mixture of the mutagenized B16 cells and the transfected cells survived significantly longer than untreated mice injected with the mutagenized B16 cells alone. Mice injected with a mixture of mutagenized B16 cells and cells transfected with DNA from unirradiated B16 cells died in shorter intervals. Based on the results of cytotoxicity assays performed in vitro, the cellular immune responses of greatest magnitude were directed toward the type of cell from which the DNA was obtained.


[Experimental comparison of the toxicity of radix Aconity Kusnezoffii and processed radix Aconity Kusnezoffii by different methods].
This paper deals with the effects of Radix Aconity Kusnezoffii and Radix Aconity Kusnezoffii processed by a new method of moistening and steaming, and by pharmacopoeial routine on acute toxicity, cardiac rhythm and respiration. The result shows that the Radix Aconity Kusnezoffii processed by new method No 1., which applies moistening in water for 48h and then heating with high pressure steam (68.65kPa, 115 degrees C) for 2h, has the advantages of lower toxicity, and lesser inhibitory effect on cardiac rhythm and respiration.


CRISPR/Cas9-Based Cellular Engineering for Targeted Gene Overexpression.
Gene and cellular therapies hold tremendous promise as agents for treating genetic disorders. However, the effective delivery of genes, particularly large ones, and expression at therapeutic levels can be challenging in cells of clinical relevance. To address this engineering hurdle, we sought to employ the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to insert powerful regulatory elements upstream of an endogenous gene. We achieved robust activation of the COL7A1 gene in primary human umbilical cord blood CD34⁺ hematopoietic stem cells and peripheral blood T-cells. CD34⁺ cells retained their colony forming potential and, in a second engineering step, we disrupted the T-cell receptor complex in T-cells. These cellular populations are of high translational impact due to their engraftment potential, broad circulatory properties, and favorable immune profile that supports delivery to multiple recipients. This study demonstrates the feasibility of targeted knock in of a ubiquitous chromatin opening element, promoter, and marker gene that doubles as a suicide gene for precision gene activation. This system merges the specificity of gene editing with the high level, sustained gene expression achieved with gene therapy vectors. We predict that this design concept will be highly transferrable to most genes in multiple model systems representing a facile cellular engineering platform for promoting gene expression.


Prognostic significance of mutant-allele tumor heterogeneity in uterine corpus endometrial carcinoma.
Uterine corpus endometrial carcinoma (UCEC) is a clinically heterogeneous disease, and this heterogeneity is associated with tumor development, clinical characteristics, and prognostic outcomes. Mutant-allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative measure to assess intra-tumor heterogeneity based on next-generation sequencing data. We aimed to explore the use of MATH as a measure for tumor heterogeneity and its prognostic role in UCEC patients. We calculated MATH scores from the available data of 560 UCEC patients from The Cancer Genome Atlas (TCGA) and investigated their correlations with clinical characteristics, genetic alterations, and overall survival. Predictive accuracy was quantified using the area under the receiver operating characteristic curve (AUC) and the index of concordance (C-index). In total, 242 MATH scores were obtained from the UCEC cohort. MATH scores were significantly related to age, race, cancer type, clinical stage, histological grade, molecular type, targeted molecular therapy, and hormonal therapy. Furthermore, the genomic pattern on the basis of MATH scores showed that mutation rates of TP53 (tumor protein p53) and ARID1A (AT-rich interaction domain 1A) were independently associated with MATH scores. Correlation analysis revealed a significantly positive association of MATH scores with the fraction of somatic copy number alteration (SCNA). Importantly, a high MATH score was significantly associated with shorter overall survival [hazard ratio (HR), 2.342; 95% confidence interval (CI), 1.110-4.942]. Multivariate Cox regression combined with stratified analysis revealed that the MATH score is an independent prognostic factor in UCEC patients under 60 years old, and predictive quantification showed the MATH score had an AUC of 0.756 and a C-index of 0.845. Our results suggest that MATH, a practical and useful way to measure intra-tumor heterogeneity, may serve as a significant biomarker for the prognosis of patients with UCEC, enabling more accurate prediction of clinical outcomes.


Review of methods of identification of high caries risk groups and individuals. Fédération Dentaire Internationale Technical Report No. 31.
The search for methods of predicting dental caries activity began during the last century. The purpose of this review was to update the report on methods of caries prediction which resulted from the 1977 workshop, sponsored by the National Institutes of Health, Washington, DC, and also to identify the methods most likely to provide effective prediction of caries risk which should be given high priority in future research. The factors that need to be considered in assessing the value of a method of predicting caries risk are the correlation coefficient between the predictions and the final caries scores and in particular an assessment of the ability of the method to recognize subjects who will develop caries (sensitivity) and to exclude those who will not (specificity). The predictive power of the method should also be known. There is, however, the risk that when predictive tests are applied to a population with decreasing caries prevalence the number classified as false positive could be increased. This may limit the cost-effectiveness of preventive technique. The requirements of a good method of predicting dental caries are that the method should be simple, inexpensive and rapid and should identify subjects who will become diseased and exclude subjects who will remain healthy. To date, a wide variety of factors have been considered in the search for an effective method of predicting caries risk, but only a few have had some success. Certain epidemiological methods have shown reasonable sensitivity but less specificity. Measures in this category include specific indicator surfaces and DMFT increment in the previous year. Among the more useful specific tests have been mutans streptococci and lactobacillus counts and measurement of saliva buffering capacity. Other methods that show some promise include the physical measurement of incipient carious lesions of enamel. The measurement of possible determinants of a multifactorial disease is extremely difficult and regardless of which single method has been tried the authors have usually concluded that it is difficult to develop a reliable method of identifying caries susceptible individuals from the method. To a lesser extent the same conclusions have been applied to methods for identifying risk groups. There does, however, appear to have been little research in which a combination of tests or methods have been used, particularly combinations of tests that involve different scientific disciplines.(ABSTRACT TRUNCATED AT 400 WORDS)


Association Of Tumour Necrosis Factor-Alpha -308 G/A Promoter Polymorphism With Susceptibility And Disease Profile Of Rheumatoid Arthritis.
Single nucleotide polymorphism underlying the auto-immune process governing the pathologic manifestations of rheumatoid arthritis has been the focus of study for quite a while. TNF-alpha -308 G/A promoter polymorphism have been reported to be responsible for a number of manifestations of rheumatoid arthritis. This case-control study was conducted at the department of Rheumatology at Pakistan Institute of Medical Sciences Islamabad from 9th May to 9th August 2019 with a focus to determine the Association of tumour necrosis factor-alpha -308 G/A promoter polymorphism with susceptibility and disease profile of rheumatoid arthritis. One hundred and fifty cases with diagnosed rheumatoid arthritis and 150 age and gender matched controls were enrolled in the study. Their genotyping was done for tumour necrosis factor-alpha - 308 G/A promoter polymorphism. The genotypic analysis showed that GG genotype was the most common genotype found in 118 cases (78.66%) followed by GA (18.66%) and AA genotype (2.6%) p=0.0096 in both cases and controls. Overall, G allele was more common than A in both cases and controls pointing towards the preponderance of G genotype in our population. (p=0.003). However, the GA genotype and A allelotype was more common among cases with rheumatoid arthritis (p <0.05). No significant association of G/A polymorphism with smoking and gender, however, within gender, males had a significantly more expression of the GA genotype and A allelotype (p <0.05). There is a significantly more expression of the GA genotype and the A allelotype of the TNF-alpha -308 G/A promoter gene in rheumatoid arthritis patients in our population. Similarly, more males, compared to females have increased expression of the GA genotype as well as the A allelotype.


Structural stability and thermoelectric performance of high quality synthetic and natural pyrites (FeS2).
Synthetic bulk and natural pyrite from the hydrothermal mine in Schönbrunn (Saxony, Germany) are confirmed to be stoichiometric FeS2 compounds and stable (for thermoelectric applications) up to ∼600 K by combined thermal, chemical, spectroscopic and X-ray diffraction analyses. Natural pyrite with a small amount (<0.6 wt%) of well-defined transition metal carbonates revealed characteristics of a nondegenerate semiconductor and is suitable as a model system for the investigation of thermoelectric performance. In the temperature range 50-600 K both natural and synthetic high quality bulk FeS2 samples show electrical resistivity and Seebeck coefficients varying within 220-5 × 10-3 Ω m and 4 - (-450) μV K-1, respectively. The large thermal conductivity (∼40 W m-1 K-1 at 300 K) is exclusively due to phononic contribution, showing a well pronounced maximum centered at ∼75 K for natural pyrite (grain size ≤5 mm). It becomes almost completely suppressed in the sintered bulk samples due to the increase of point defect concentration and additional scattering on the grain boundaries (grain size ≤100 μm). The thermoelectric performance of pure pyrite with ZT ∼ 10-6 at 600 K is indeed by a factor of ∼1000 worse than those reported earlier for some minerals and synthetic samples.


Successful cardiac resynchronization therapy after cardiac surgery.
Cardiac resynchronization therapy improves symptoms and survival in chronic heart failure patients, but has been poorly studied in the acute heart failure setting. We report the case of successful cardiac resynchronization therapy in the early postoperative period after cardiac surgery in a patient with left bundle branch block and proven ventricular dyssynchrony.


Pharmacogenetics of the S-oxidation of S-carboxymethyl-L-cysteine.
The pharmacogenetics of S-carboxymethyl-L-cysteine (SCMC) have been studied in detail. When results from administration of SCMC to 200 volunteers were analysed, there was seen to be a wide interindividual variation in the percentage of sulphoxide metabolites excreted. Computer assisted analysis suggested that the population distribution observed could be most economically represented as two overlapping Gaussian distributions with the smaller mode representing poor sulphoxidisers. This phenomenon appears to be largely genetic in origin and to behave as though controlled by one autosomal recessive gene, but environmental factors may also be important. Poor sulphoxidisers seem to be overrepresented in certain patient populations with chronic diseases. These findings are discussed in terms of oxidative metabolism of sulphur-containing compounds.


Nondestructive measurement of fruit and vegetable quality.
We review nondestructive techniques for measuring internal and external quality attributes of fruit and vegetables, such as color, size and shape, flavor, texture, and absence of defects. The different techniques are organized according to their physical measurement principle. We first describe each technique and then list some examples. As many of these techniques rely on mathematical models and particular data processing methods, we discuss these where needed. We pay particular attention to techniques that can be implemented online in grading lines.


Development of a specific method to evaluate 8-hydroxy, 2-deoxyguanosine in sperm nuclei: relationship with semen quality in a cohort of 94 subjects.
Oxidative stress (OS) is involved in many disoders including male infertility. Human spermatozoa are very sensitive targets of reactive oxygen species (ROS) and most sperm functions are impaired in the case of OS. In addition unbalanced production of ROS is considered one of the most important causes of sperm DNA fragmentation, a semen trait of infertile men. The relationship between oxidative damage and semen quality is partially controversial, probably due to the different methods and/or targets used to reveal the OS. In this study, by fluorescence microscopy and flow cytometry, we compared two methods to reveal 8-hydroxy,2-deoxyguanosine (8-OHdG), the hallmark of oxidative DNA damage: an immunofluorescence method and the commercial OxyDNA kit. We found that although both methods localized the labelling in sperm nuclei they yielded different measures, and only with the immunofluorescence method was the labelling specific for sperm 8-OHdG. The immunofluorescence method, coupled to flow cytometry, was thus selected to analyse the 8-OHdG content in semen samples from 94 subfertile patients and to investigate the relationship with semen quality. We found that the percentages of spermatozoa with 8-OHdG (mean±s.d., 11.4±6.9%) were related to sperm count (Pearson's correlation coefficient (r)=-0.27, P=0.04 (ANOVA and student's t-test)), motility (progressive: r=-0.22, P=0.04; non-progressive: r=0.25, P=0.01), and normal morphology (r=-0.27, P=0.01). In conclusion, we demonstrate that immunofluorescence/flow cytometry is a reliable and specific method to detect 8-OHdG at single-cell level and show that oxidative damage only partially overlaps poor semen quality, suggesting that it could provide additional information on male fertility with respect to routine semen analysis.


Physicians are different when they learn communication skills: influence of the locus of control.
Although it is widely recognised that educational interventions may be more effective for people with an 'internal' Locus of Control (who believe that life outcomes are controlled by their own characteristics or actions) compared to people with an 'external' Locus of Control (who believe that life outcomes are controlled by external forces such as luck, fate or others), no study has yet assessed the influence of physicians' Locus of Control (LOC) on communication skills learning. This study aims to test the hypothesis that, in a communication skills training program, physicians with an 'internal' LOC would demonstrate communication skills acquisition to a greater degree than those with an 'external' LOC. A non-randomised longitudinal intervention study was conducted between January 1999 and April 2001. Sixty-seven volunteer physicians from private and institutional practice in Belgium participated in a learner-centred, skills-focused, practice-oriented communication skills training program. Communication skills changes were assessed in 2 standardised simulated interviews before and after training (one two-person and one three-person interview). Communication skills were assessed using the Cancer Research Campaign Workshop Evaluation Manual. Physicians' LOC was assessed using the Rotter I-E scale. Communication skills changes of the upper and lower third of physicians in respect of their scores on this scale were compared using group by time repeated measures of variance. In the two-person and three-person interviews, changes in the use of open directive questions were more important among physicians with an "internal" LOC compared with changes observed among physicians with an 'external' LOC (P=0.066 and P=0.004, respectively). In the three-person interview, changes in the use of directive questions, assessing functions and moderate feelings stated explicitly were more important among physicians with an 'internal' LOC compared with changes observed among physicians with an 'external' LOC (P= 0.001; P=0.002 and P=0.011 respectively). This study shows that physicians' LOC is a psychological characteristic that could influence the efficacy of a communication skills training program. This evidence supports the idea that a psychological characteristic such as 'internal' LOC may facilitate communication skills acquisition through physicians' belief that communication with patients may be controlled by physicians themselves.


Epigallocatechin gallate increases the formation of cytosolic lipid droplets and decreases the secretion of apoB-100 VLDL.
Epigallocatechin gallate (EGCG) increases the formation of cytosolic lipid droplets by a mechanism that is independent of the rate of triglyceride biosynthesis and involves an enhanced fusion between lipid droplets, a process that is crucial for their growth in size. EGCG treatment reduced the secretion of both triglycerides and apolipoprotein B-100 (apoB-100) VLDLs but not of transferrin, albumin, or total proteins, indicating that EGCG diverts triglycerides from VLDL assembly to storage in the cytosol. This is further supported by the observed increase in both intracellular degradation of apoB-100 and ubiquitination of the protein (indicative of increased proteasomal degradation) in EGCG-treated cells. EGCG did not interfere with the microsomal triglyceride transfer protein, and the effect of EGCG on the secretion of VLDLs was found to be independent of the LDL receptor. Thus, our results indicate that EGCG promotes the accumulation of triglycerides in cytosolic lipid droplets, thereby diverting lipids from the assembly of VLDL to storage in the cytosol. Our results also indicate that the accumulation of lipids in the cytosol is not always associated with increased secretion of VLDL.


Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers.
Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE-preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655-664 2018 AASLD.


Impact of oxidative stress on neuronal survival.
1. Reactive oxygen species and oxidative state are slowly gaining acceptance in having a physiological relevance rather than just being the culprits in pathophysiological processes. The control of the redox environment of the cell provides for additional regulation in relation to signal transduction pathways. Conversely, aberrant regulation of oxidative state manifesting as oxidative stress can predispose a cell to adverse outcome. 2. The phosphatidylinositol 3-kinase/akt pathway is one such pathway that is partially regulated via oxidative state and, in an oxidative stress paradigm such as ischaemic-reperfusion injury, may be inactivated, which can lead to exacerbation of cell death. 3. Activation of nuclear factor (NF)-kappaB has been associated with oxidative stress. The role of NF-kappaB in neuronal cell death is widely debated, with major studies highlighting both a pro- and anti-apoptotic role for NF-kappaB, with the outcome being region, stimulus, dose and duration specific. 4. Oxidative state plays a key role in the regulation and control of numerous signal transduction pathways in the cell. Elucidating the mechanisms behind oxidative stress-mediated neuronal cell death is important in identifying potential putative targets for the treatment of diseases such as stroke.


Bis-anthracene fused porphyrins: synthesis, crystal structure, and near-IR absorption.
Synthesis of fused bis-anthracene porphyrin monomers and dimers has been achieved by oxidative ring closure using FeCl(3) and Sc(OTf)(3)/DDQ, respectively. The fused compounds display red-shifted absorption spectra with maxima in the near-IR at 973 and 1495 nm, respectively, and small electrochemical HOMO-LUMO gaps. The crystal structure of the fully fused bis-anthracene porphyrin shows that it has a regular planar pi-system.


Retrograde horseradish peroxidase tracing combined with localization of choline acetyltransferase immunoreactivity.
Localization of choline acetyltransferase (ChAT) immunoreactivity in rodent brain (AI Levey, DM Armstrong, SF Atweh, RD Terry, BH Wainer: J Neurosci 3 1, 1983) with a monoclonal antibody (Ab8) has been previously reported. Now a procedure for combining ChAT immunohistochemistry with retrograde tracing for the purpose of mapping cholinergic pathways is presented. Rats were injected with horseradish peroxidase-wheat germ agglutinin in the tongue and cerebral cortex. Sections from their perfusion-fixed brains were reacted with 3,3'-diaminobenzidine (DAB)/H2O2/cobalt acetate followed by ChAT localization with monoclonal antibody Ab8 using the peroxidase-antiperoxidase method and visualization using DAB/H2O2. Double-labeled cells were visualized with black punctate staining (retrograde tracer) on a diffuse brown cytoplasmic background (ChAT immunoreactivity) in the hypoglossal nucleus and ventral telencephalon (substantia innominata-nucleus basalis). Conditions of fixation, histochemistry, and immunohistochemistry that contribute to optimal resolution for this procedure are discussed.


[Physiotherapy in early rehabilitation of patients with bone sarcomas after arthroplasty of large bones and joints].
The modern method of treating patients with tumor lesions of the bones is the replacement of large bones and joints with the inclusion of reconstructive plastic component. The main functional postoperative disorders of this method (limitation of mobility in the operated joint, pain, muscle hypotrophy and edema of the operated limb) obstruct the ability of patients to return to a full life, which makes their early rehabilitation extremely urgent. Orthopedics uses a number of physical factors for this. The literature presents data on the absence of negative effects of low-frequency electro- and magnetotherapy in the treatment of late complications of oncopedic surgery on a number of bone sarcomas, which allowed them to be included in early rehabilitation for the first time. Development of a complex of early rehabilitation of patients with bone tumors after arthroplasty of large bones and joints and evaluation of its effectiveness. A prospective, open, nonrandomized, controlled study included 36 patients aged 19-67 years (Me 42 years old) with primary malignant and metastatic bone tumors who underwent endoprosthesis replacement of large bones and joints with the inclusion of reconstructive plastic component (plastic by displaced muscles, synthetic mesh) and received local low-frequency magnetotherapy, low-intensity infrared laser radiation, electroneuromyostimulation and therapeutic exercises. Physiotherapy began from the first day after the operation and lasted for 10 days. To assess the functional result, the international MSTS scale was used. The combined use of the reconstructive plastic component during radical surgery and physiotherapy made it possible to obtain good functional result at 63,9% of patients, satisfactory functional results in 36.1% of patients according to the MSTS scale at the time of discharge. The function of the saved limb in 10 patients after distal femoral resection with knee replacement was 80% of normal function, in 7 patients after proximal tibia resection - 72%; in 13 patients after proximal resection of the femur with hip replacement - 59%; in 5 patients after proximal resection of the humerus with endoprosthetics of the shoulder joint - 61.3%; and in 1 patient after proximal resection of the ulna with endoprosthetics of the elbow joint - 70%. The multidisciplinary approach to the early rehabilitation of patients with bone tumors made it possible to achieve functional results in a short time, reduce the time spent by patients in the surgical department without increasing the number of postoperative complications. Based on the preliminary obtained results, it is necessary to continue the study on a larger number of patients and with a longer follow-up period.


IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor.
Targeted monoclonal antibody therapy is an important strategy in cancer therapeutics. Among the most promising characteristics of therapeutic targets are those that modulate the growth and survival of malignant neoplasms and their sensitivity to anticancer therapies. The insulin-like growth factor-I receptor (IGF-IR) is overexpressed in many types of solid and hematopoietic malignancies, and has been implicated as a principal cause of heightened proliferative and survival signaling. IGF-IR has also been shown to confer resistance to cytotoxic, hormonal, and targeted therapies, suggesting that therapeutics targeting IGF-IR may be effective against a broad range of malignancies. IMC-A12 (ImClone Systems Incorporated), a fully human monoclonal IgG1 antibody that binds with high affinity to the IGF-IR, inhibits ligand-dependent receptor activation and downstream signaling. IMC-A12 also mediates robust internalization and degradation of the IGF-IR. In human tumor xenograft models, IGF-IR blockade by IMC-A12 results in rapid and profound growth inhibition of cancers of the breast, lung, colon, and pancreas, and many other neoplasms. Although promising single-agent activity has been observed, the most impressive effects of targeting the IGF-IR with IMC-A12 have been noted when this agent was combined with cytotoxic agents or other targeted therapeutics. The results with IMC-A12 to date suggest that it may be an effective therapeutic in a diverse array of oncologic indications.


Validation of ELISA with recombinant antigens in serological diagnosis of canine Leishmania infantum infection.
Dogs are the main peridomiciliary reservoir of Leishmania infantum thus the correct diagnosis of infection is essential for the control of the transmission and treatment as well. However, the diagnosis is based on serological assays that are not fully effective. We aimed to establish an effective serological assay for the diagnosis of L. infantum infected dogs using Leishmania-derived recombinant antigens. Leishmania derived rK39-, rK28-, rKR95-based enzyme-linked immunosorbent assay (ELISA) was standardized using symptomatic and asymptomatic L. infantum-infected dogs. Then 2,530 samples from inquiry in endemic areas for VL were evaluated and the results compared with recommended assays by the Brazilian Ministry of Health (MH algorithm). Further samples from a cohort of 30 dogs were searched. For rK39-, rK28- and rKR95-ELISA the sensitivity was around 97% and specificity 100%. The positivity of these three ELISA in the inquiry samples was 27-28%, around 10% higher than the assays currently in use. When cohort samples were searched, we observed likely false-negative results (> 65%) with supposedly negative samples that turned positive six months later with the assays in use (MH algorithm). For the diagnosis of L. infantum-infected dogs, rK39-based ELISA showed better diagnostic performance than other assays in use in Brazil and worldwide.


Receptor modifications in vulvar dystrophies before and after treatment with topical hormones: comparison between the dextran-charcoal technique and immunohistochemical evaluation.
The objective of the study was first to quantify estrogen receptors (ERs) and progesterone receptors (PRs) in dystrophic vulvar tissue before and after topical hormone treatment in an attempt to evaluate whether receptor modifications occurred. Second we compared quantitative analysis with immunohistochemical staining of the vulvar specimens. We studied 115 vulvar specimens obtained from 75 consenting women ranging from 21 to 78 years of age. Of the patients, 12 had histologically normal vulvar skin, 45 had vulvar dystrophies that were not treated by topical steroid therapy, 28 patients had vulvar dystrophies that were treated by testosterone propionate (TP) 2%, 12 patients had vulvar dystrophies that were treated by progesterone in hydroalcoholic gel and 18 patients had vulvar malignant tumors. For immunohistochemical analysis we considered 25 cases of vulvar dystrophies: 11 cases of squamous hyperplasia (SH) and 14 cases of lichen sclerosus (LS). Among these 25 cases, 15 (5 SH and 10 LS) were treated with TP 2%. After treatment of the vulvar dystrophies with progesterone, the positivity of ERs decreased (58.3% vs 77.8%). After treatment of the vulvar dystrophies with TP 2%, the positivity of PRs significantly decreased (14.3% vs 68.9%) whereas after treatment with progesterone the positivity of PRs increased (83.3%). The immunohistochemical study showed some differences in comparison to the quantitative study. In fact we found low basal positivity especially for PRs (16% vs 68.9% of the quantitative study). This finding was due to the use of a cutoff of at least ++ in order to increase the specificity. After treatment with TP 2%, we observed an increase of immunohistochemical positivity for ERs even in cases that were negative before treatment and a lack of PRs even in cases that were positive before treatment. These data demonstrate the efficacy of androgen therapy with TP 2% in vulvar dystrophies with increased trophism due to the increase of ERs.


[Pulmonary embolism complicated with right-sided intracardiac thrombus entrapped in a patent foramen ovale].
With the increasing possibilities of and clinical demand for diagnostic imaging in the management of acute cardiovascular disease, the probability of uncovering complicated cases increases. These cases are often challenging to the clinician in determining the best method of treatment. We present a case of pulmonary embolism in which an intracardiac thrombus entrapped in a patent foramen ovale without penetrating it was discovered. The patient received thrombolytic therapy without complications and was discharged in good condition six days after thrombolysis.


[Effect of estrogen-deficiency on expression of osteoprotegerin in alveolar bone: experiment with rats with periodontitis].
To investigate the effects of estrogen-deficiency upon the expression of osteoprotegerin (OPG) in alveolar bone so as to clarify the role of estrogen in alveolar bone metabolism. Fifty-three SD rats were randomly divided into 3 groups: OVX group (n=18) undergoing bilateral ovariectomy, OVX + E2 group (n=18), undergoing bilateral ovariectomy and subcutaneous injection of estradiol once 3 days since day 2 after the operation, and sham operation group (n=17) undergoing sham operation. Four weeks after the operation periodontal ligature was conducted and high-sugar diet was fed to establish periodontitis models. Four weeks later the rats were killed. The morphological changes and expression of OPG in alveolar bone were observed by light microscopy and immunohistochemistry. All the rats showed sparseness of bone trabeculae in alveolar bone and osteoclasts and lacuna at the surface of alveolar bone, especially the rate of the group OVX. The A values (absorption of the OPG expression) in the alveolar bone of the OVX groups was 27 854 +/- 5246, significantly lower than those of the sham operation group and OVX + E2 group (38 799 +/- 6228 and 37 146 +/- 6394 respectively, both P < 0.05) without significant difference between the sham operation group and OVX + E2 group (P > 0.05). Estrogen deficiency decreases the expression of OPG in alveolar bone, and enhances the absorption of alveolar bone.


[Treatment of extensive traumatic loss of substance of the foot and ankle by free flaps. Apropos of 7 clinical cases].
The authors report 7 cases of extensive skin defects of the foot and/or the ankle treated by using a free flap. All cases presented with major trauma of the lower limb with obvious exposure of bone and joint tissues. The skin defect was covered: as an emergency in 4 cases; within the 48 hours following the trauma in 3 cases; on the 7th day after the injury in 1 case. The free flap used was: the latissimus dorsi muscle, 2 cases; the gracilis muscle, 1 case; the serratus anterior muscle, 1 case; the greater omentum, 2 cases. Arterial microanastomoses were performed onto the anterior tibial or pedal arteries, in 4 cases, and onto the posterior tibial artery in 4 cases. Except for 1 failure on the 8th day after the operation due to thrombosis of the venous anastomosis, requiring arthrodesis of the ankle, the outcome was favorable in all other cases, free of osteitis or arthritis. The authors emphasize the importance of covering defects the lower limb as quickly as possible, ideally as an emergency, when a free flap is required.


Long-term mood/antidepressant effects of quetiapine extended-release formulation: an open-label, non-controlled extension study in Japanese patients with bipolar depression.
In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment. This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale. The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified. The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression. ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).


[Control of terminal follicular maturation during the follicular phase in domestic mammals].
Terminal follicular maturation in the ovine and the bovine species involves growth and differentiation processes in follicles between 1-2 mm diameter and the preovulatory stage. During this maturation, the follicle acquires the ability to ovulate and the oocyte becomes able to be fertilized and to develop after fertilization. Selection of ovulatory follicles results from the integration of different parameters such as the circulating levels of gonadotropins, the structure of follicular populations and the sensitivity of the hypothalamo-pituitary axis to ovarian hormones. Differences between follicles for FSH and LH responsiveness can be amplified by paracrine intrafollicular regulations. These mechanisms are probably determinant for selection of ovulatory follicles.


QUASAR--scoring and ranking of sequence-structure alignments.
Sequence-structure alignments are a common means for protein structure prediction in the fields of fold recognition and homology modeling, and there is a broad variety of programs that provide such alignments based on sequence similarity, secondary structure or contact potentials. Nevertheless, finding the best sequence-structure alignment in a pool of alignments remains a difficult problem. QUASAR (quality of sequence-structure alignments ranking) provides a unifying framework for scoring sequence-structure alignments that aids finding well-performing combinations of well-known and custom-made scoring schemes. Those scoring functions can be benchmarked against widely accepted quality scores like MaxSub, TMScore, Touch and APDB, thus enabling users to test their own alignment scores against 'standard-of-truth' structure-based scores. Furthermore, individual score combinations can be optimized with respect to benchmark sets based on known structural relationships using QUASAR's in-built optimization routines.


Opacification of the thoracic aorta after venous injection of sonicated albumin microbubbles. Implications for aortic dissection.
This study was designed to assess the feasibility of thoracic aorta opacification after intravenous injection of sonicated albumin microbubbles in patients with and without aortic dissection. Twenty-one patients were studied by transesophageal echocardiography. In 11 patients without aortic dissection, the opacification of the left ventricular outflow tract, aortic root and descending aorta was evaluated. Ten patients with aortic dissection were studied to assess perfusion of the true and false lumen. The left ventricular outflow tract, aortic root and descending aorta were opacified in all patients, with a systolic increase in contrast at visual analysis and at videodensitometry. The differentiation between false and true lumen was improved and was crucial in 1 case of type A chronic dissection. The intimal tear was detected in 7/9 cases by color Doppler vs 9/9 cases by contrast echocardiography. The noninvasive ultrasound opacification of thoracic aorta is feasible and may improve the diagnosis of aortic dissection.


[The significance of exometabolites in the formation and operation of the soybean-rhizobium symbiosis].
The effect of various inoculates of the soybean-specific strain of nodule bacteria Bradyrhizobium japonicum 634b (unwashed cells, cells washed from the exopolysaccharide-protein complex, and cells combined with the complex) on the formation and operation of soybean-rhizobium symbiosis. It was shown that addition of the exopolysaccharide-protein complex doubled the ability of the microsymbiont to form nodules, nodule weight, and the nitrogenase activity of the nodules. Bradyrhizobium japonicum 634b cells washed from exometabolites had lower indices of symbiotic activity than their intact counterparts.


Canadian dentists' opinions on publicly financed dental care.
The aim of this study was to inform policy leaders of the opinions of Canada's major dental care service provider regarding publicly financed dental care. Using provincial/territorial dental regulatory authority listings, a 26-item questionnaire was sent to a representative sample of Canadian dentists (n = 2219, response rate = 45.8 percent). Descriptive statistics were produced, and bivariate and multivariate logistic regressions were conducted to assess what predicts dentists' responses. Canadian dentists support governmental involvement in dental care, preferring investments in prevention to direct delivery. The majority of dentists have less than 10 percent of their practice represented by publicly insured patients, with a small minority having greater than 50 percent. The majority would accept new publicly insured patients, preferring fee for service remuneration. Dentists generally appear dissatisfied with public forms of third-party financing. Dentists prefer a targeted effort at meeting public needs and are influenced in their opinions largely in relation to ideology. In order to move forward, policy leaders will need to devote some attention to the influence and complexity of public and private tensions in dentistry At the very least, public and private practitioners must come to appreciate each other's challenges and balance public and private expectations in public programming.


Skin occlusion: treatment or drug-like device?
The effects of occlusion on skin function are described and reviewed. Occlusion seems to be not only a device applied on the skin surface, but, under certain conditions, a powerful treatment capable of inducing several changes on epidermal metabolism, skin flora, sweat glands and epidermal morphology.


Fontan-Associated Liver Disease: Pathophysiology, Staging, and Management.
Fontan-associated liver disease is the term used to encompass the disorders arising from abnormal hemodynamic alterations and systemic venous congestion after the Fontan procedure. The histological changes produced in the liver are similar but not equivalent to those seen in other forms of cardiac liver disease. While the natural history of this form of liver disease is poorly established, many Fontan patients ultimately develop portal hypertension-related complications such as ascites, esophageal varices, malnutrition, and encephalopathy. Fontan survivors also show an elevated risk of hepatocellular carcinoma. Adequate staging of the liver damage is essential to anticipate screening strategies and improve global management.


Coordinated peptidoglycan synthases and hydrolases stabilize the bacterial cell wall.
Peptidoglycan (PG) defines cell shape and protects bacteria against osmotic stress. The growth and integrity of PG require coordinated actions between synthases that insert new PG strands and hydrolases that generate openings to allow the insertion. However, the mechanisms of their coordination remain elusive. Moenomycin that inhibits a family of PG synthases known as Class-A penicillin-binding proteins (aPBPs), collapses rod shape despite aPBPs being non-essential for rod-like morphology in the bacterium Myxococcus xanthus. Here, we demonstrate that inhibited PBP1a2, an aPBP, accelerates the degradation of cell poles by DacB, a hydrolytic PG peptidase. Moenomycin promotes the binding between DacB and PG and thus reduces the mobility of DacB through PBP1a2. Conversely, DacB also regulates the distribution and dynamics of aPBPs. Our findings clarify the action of moenomycin and suggest that disrupting the coordination between PG synthases and hydrolases could be more lethal than eliminating individual enzymes.


Expanded microbial genome coverage and improved protein family annotation in the COG database.
Microbial genome sequencing projects produce numerous sequences of deduced proteins, only a small fraction of which have been or will ever be studied experimentally. This leaves sequence analysis as the only feasible way to annotate these proteins and assign to them tentative functions. The Clusters of Orthologous Groups of proteins (COGs) database (http://www.ncbi.nlm.nih.gov/COG/), first created in 1997, has been a popular tool for functional annotation. Its success was largely based on (i) its reliance on complete microbial genomes, which allowed reliable assignment of orthologs and paralogs for most genes; (ii) orthology-based approach, which used the function(s) of the characterized member(s) of the protein family (COG) to assign function(s) to the entire set of carefully identified orthologs and describe the range of potential functions when there were more than one; and (iii) careful manual curation of the annotation of the COGs, aimed at detailed prediction of the biological function(s) for each COG while avoiding annotation errors and overprediction. Here we present an update of the COGs, the first since 2003, and a comprehensive revision of the COG annotations and expansion of the genome coverage to include representative complete genomes from all bacterial and archaeal lineages down to the genus level. This re-analysis of the COGs shows that the original COG assignments had an error rate below 0.5% and allows an assessment of the progress in functional genomics in the past 12 years. During this time, functions of many previously uncharacterized COGs have been elucidated and tentative functional assignments of many COGs have been validated, either by targeted experiments or through the use of high-throughput methods. A particularly important development is the assignment of functions to several widespread, conserved proteins many of which turned out to participate in translation, in particular rRNA maturation and tRNA modification. The new version of the COGs is expected to become an important tool for microbial genomics.


Sources of discrepancies in the diagnosis of Hodgkin's disease by fine needle aspiration.
The aim of this study was to assess the value of Fine Needle Aspiration (FNA) Cytology in the diagnosis of Hodgkin's Disease (HD) and to identify the sources and nature of the inaccuracies related to this procedure. We retrospectively studied all cases cytologically diagnosed in our laboratory as HD during a five year period (1990-1994). We also traced cases in which FNA cytology failed to reveal HD and where a subsequent HD diagnosis was made by histology. Of the 99 cases studied, a histological report was available for 93. In 82 cases FNA was carried out as part of the initial evaluation. In the remaining 17 cases the diagnosis of HD was known and FNA was performed in order to confirm or exclude a relapse. The results included 4 false positive for HD, 5 false negative and 3 HD-suspicious cases (only one of which proved histologically to be HD while the remaining two were other neoplasms). The re-evaluation of the last 12 cases identified 3 different sources of error: a) Material adequacy criteria; b) Sampling techniques; c) Interpretation.


Computer-based patient monitoring systems. Use in research and clinical practice.
The use of new technologies, such as computers, in the management of diabetes has changed dramatically over the past decade. The development of the memory-based reflectance meter, telephone modems for the transmission of self-monitored blood glucose, and computer programs to aggregate and analyze data have significantly altered approaches to diabetes care. The clinical application of these systems is just now being evaluated. Initial data suggest that these systems enhance treatment, improve patient performance, assist in collection and representation of accurate and reliable data, and may be associated with improved metabolic control.