N-heterocyclic carbene induced reductive coupling of phosphorus tribromide. Isolation of a bromine bridged P-P bond and its subsequent reactivity.
The room temperature reaction of a 1 : 1 mixture of phosphorus tribromide (PBr3) and the N-heterocyclic carbene 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr) quantitatively affords the Lewis acid-base adduct (IPr)PBr3 (1). Interestingly, when 1 is heated between 55 and 65 °C for a period of several days, dark red crystals slowly begin to form in the reaction vessel accompanied by the release of bromine. The resulting crystalline sample, [P2(IPr)2Br3]Br ([2]Br), results from the reductive coupling of two equivalents of 1, and contains a cationic moiety with a P-P bond that is bridged by a bromine atom. Anion exchange reactions with Na[BArF4] (BArF4 = B(3,5-{CF3}2C6H3)4) afford [2][BArF4]. Abstraction of two equivalents of bromine allows for the isolation of the unprecedented dicationic species [P2(IPr)2Br2]2+ (3) which was isolated and structurally authenticated as two different [BArF4]- salts. Reaction of 2 with mild reductants such as SnBr2 or tetrakis(dimethylamino)ethylene (TDAE) affords [P2(IPr)2Br]+ (4) and the known radical cation [P2(IPr)2]˙+ (5), respectively. These studies show that relatively weak P-Br bonds present in compounds 1-4 can be cleaved in a straightforward manner to afford low oxidation state compounds in high yields.


Neural mechanisms relevant to the design of an auditory prosthesis. Location and electrical characteristics.
A cochlear prosthesis designed to electrically stimulate eighth nerve fibers in deaf subjects was studied in acute guinea pig preparations. The prosthesis, which consisted of two pairs of platinum-iridium electrodes, was inserted into the scala tympani through the round window. The electrical impedances of different current paths and their effectiveness in evoking neural responses in the central auditory system are compared. Assuming lumped neural elements, the results indicate that the sites of neural excitation lie outside the scala tympani. Frequency-response characteristics of neural excitation are in agreement with resistive spread of current through tissue to the site of stimulation. Neural membrane characteristics similar to those previously studied in nonmammalian nerves seem to account for the response initiation.


Development and characterization of an automated high throughput screening method for optimization of protein refolding processes.
Optimization of protein refolding parameters by automated, miniaturized, and parallelized high throughput screening is a powerful approach to meet the demand for fast process development with low material consumption. In this study, we validated methods applicable on a standard liquid handling robot for screening of refolding process parameters by dilution of denatured lysozyme in refolding buffer systems. Different approaches for the estimation of protein solubility and folding were validated concerning resolution and compatibility with the robotic system and with the complex buffer and protein structure composition. We established an indirect method to assess soluble lysozyme concentration independent of matrix effects and protein structure varieties by automated separation of aggregated protein, resolubilization, and measurement of absorption at 280 nm. Using this nonspecific solubility assays the correlation between favorable parameters for high active and soluble lysozyme yields were evaluated. An overlap of good refolding buffer compositions was found provided that the redox environment was controlled with redox reagents. In addition, the need to control unfolding conditions like time, temperature, lysozyme, and dithiothreitol concentration was pointed out as different feedstocks resulted in different refolding yields.


Postpandemic Evaluation of the Eco-Efficiency of Personal Protective Equipment Against COVID-19 in Emergency Departments: Proposal for a Mixed Methods Study.
The COVID-19 pandemic has had a profound impact on emergency department (ED) care in Canada and around the world. To prevent transmission of COVID-19, personal protective equipment (PPE) was required for all ED care providers in contact with suspected cases. With mass vaccination and improvements in several infection prevention components, our hypothesis is that the risks of transmission of COVID-19 will be significantly reduced and that current PPE use will have economic and ecological consequences that exceed its anticipated benefits. Evidence is needed to evaluate PPE use so that recommendations can ensure the clinical, economic, and environmental efficiency (ie, eco-efficiency) of its use. To support the development of recommendations for the eco-efficient use of PPE, our research objectives are to (1) estimate the clinical effectiveness (reduced transmission, hospitalizations, mortality, and work absenteeism) of PPE against COVID-19 for health care workers; (2) estimate the financial cost of using PPE in the ED for the management of suspected or confirmed COVID-19 patients; and (3) estimate the ecological footprint of PPE use against COVID-19 in the ED. We will conduct a mixed method study to evaluate the eco-efficiency of PPE use in the 5 EDs of the CHU de Québec-Université Laval (Québec, Canada). To achieve our goals, the project will include four phases: systematic review of the literature to assess the clinical effectiveness of PPE (objective 1; phase 1); cost estimation of PPE use in the ED using a time-driven activity-based costing method (objective 2; phase 2); ecological footprint estimation of PPE use using a life cycle assessment approach (objective 3; phase 3); and cost-consequence analysis and focus groups (integration of objectives 1 to 3; phase 4). The first 3 phases have started. The results of these phases will be available in 2023. Phase 4 will begin in 2023 and results will be available in 2024. While the benefits of PPE use are likely to diminish as health care workers' immunity increases, it is important to assess its economic and ecological impacts to develop recommendations to guide its eco-efficient use. PROSPERO CRD42022302598; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=302598. DERR1-10.2196/50682.


[Ageing and cardiac function. Is there a role of physical exercise?].
Ageing of the human heart is characterized by morphological, functional and metabolic changes regardless the development of ischemic heart disease. Physical exercise is in general considered capable to counteract the onset of these changes; nevertheless short-term interventions and cross sectional studies in older individuals questioned the possibility that physical exercise may revert these alterations. Metabolic factors, development of overt cardiac diseases and probably the timing of the intervention with physical exercise during the life-span of a single individual may explain the controversial results reported in the literature.


Gramella salexigens sp. nov., isolated from seawater.
A Gram-stain-negative, rod-shaped, aerobic bacterial strain, designated LPB0144T was isolated from the seawater of South Sea, Korea. The 16S rRNA gene sequence was found to share the highest sequence similarity to Gramella sediminilitoris GHTF-27T (97.7 %) and the strain branched within the radiation of the genus Gramella in phylogenetic trees. Thus, the taxonomic position of the novel isolate was investigated using a polyphasic approach and complete genome sequencing. Strain LPB0144T has a circular chromosome of 2.98 Mb with DNA G+C content of 38.2 mol%. The genome includes 2604 protein-coding genes and three copies of rRNA operons. The detected respiratory quinone (MK-6) and the major polar lipid (phosphatidylethanolamine) resemble the chemotaxonomic profile of other Gramella species. The major cellular fatty acid profile (iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 3-OH and anteiso-C15 : 0) is also within the range of Gramella, but detailed composition and amounts were found to be different from those of closely related neighbours. Many biochemical and physiological characteristics also distinguished the isolate from other species within the genus Gramella. On the basis of polyphasic taxonomic data obtained here, we propose strain LPB0144T as a novel Gramella species, for which the name Gramella salexigens sp. nov. is proposed. The type strain is LPB0144T (=KACC 18894T=JCM 31560T).


Comparative effectiveness of treatment options for subacromial shoulder conditions: a systematic review and network meta-analysis.
There are currently many treatment options for patients with subacromial shoulder conditions (SSCs). Clinical decision-making regarding the best treatment option is often difficult. This study aims to evaluate the comparative effectiveness of treatment options for relieving pain and improving function in patients with SSCs. Eight databases [including MEDLINE, Embase, CINAHL, AMED, PEDro, Cochrane Database of Systematic Reviews and World Health Organization (WHO) International Clinical Trials Registry] were searched from inception until April 2020. Randomised clinical/controlled trials of adult patients investigating the effects of nonsurgical (e.g. corticosteroid injections, therapeutic exercise, shockwave therapy) and surgical treatment for SSCs, compared with each other, placebo, usual care or no treatment, were retrieved. Pairs of reviewers screened studies independently, quality appraised eligible studies using the Cochrane risk of bias tool, extracted and checked data for accuracy. Primary outcomes were pain and disability in the short term (⩽3 months) and long term (⩾6 months). Direct and indirect evidence of treatment effectiveness was synthesised using random-effects network meta-analysis. The review identified 177 eligible trials. Summary estimates (based on 99 trials providing suitable data, 6764 patients, 20 treatment options) showed small to moderate effects for several treatments, but no significant differences on pain or function between many active treatment comparisons. The primary analysis indicated that exercise and laser therapy may provide comparative benefit in terms of both pain and function at different follow-up time-points, with larger effects found for laser in the short term at 2-6 weeks, although direct evidence was provided by one trial only, and for exercise in the longer term [standardised mean difference (SMD) 0.39, 95% confidence interval (CI) 0.18, 0.59 at 3-6 months] compared with control. Sensitivity analyses excluding studies at increased risk of bias confirmed only the comparative effects of exercise as being robust for both pain and function up until 3-month follow-up. Current evidence shows small to moderate effect sizes for most treatment options for SSCs. Six treatments had a high probability of being most effective, in the short term, for pain and function [acupuncture, manual therapy, exercise, exercise plus manual therapy, laser therapy and Microcurrent (MENS) (TENS)], but with low certainty for most treatment options. After accounting for risk of bias, there is evidence of moderate certainty for the comparative effects of exercise on function in patients with SSCs. Future large, high-quality pragmatic randomised trials or meta-analyses are needed to better understand whether specific subgroups of patients respond better to some treatments than others.


First outbreak of Zika virus in the continental United States: a modelling analysis.
Since 2015, Zika virus (ZIKV) has spread throughout Latin and Central America. This emerging infectious disease has been causing considerable public health concern because of severe neurological complications, especially in newborns after congenital infections. In July 2016, the first outbreak in the continental United States was identified in the Wynwood neighbourhood of Miami-Dade County, Florida. In this work, we investigated transmission dynamics using a mathematical model calibrated to observed data on mosquito abundance and symptomatic human infections. We found that, although ZIKV transmission was detected in July 2016, the first importation may have occurred between March and mid-April. The estimated highest value for R0 was 2.73 (95% confidence interval (CI): 1.65-4.17); the attack rate was 14% (95% CI: 5.6-27.4%), with 15 (95% CI: 6-29) pregnant women involved and a 12% probability of infected blood donations. Vector control avoided 60% of potential infections. According to our results, it is likely that further ZIKV outbreaks identified in other areas of Miami-Dade County were seeded by commuters to Wynwood rather than by additional importation from international travellers. Our study can help prepare future outbreak-related interventions in European areas where competent mosquitoes for ZIKV transmission are already established.


Melatonin Prevents against Ethanol-Induced Liver Injury by Mitigating Ferroptosis via Targeting Brain and Muscle ARNT-like 1 in Mice Liver and HepG2 Cells.
The circadian clock acts a pivotal part in human daily physiology and metabolism. Excess alcohol consumption disturbs the circadian rhythm of several metabolism-related genes of the liver. Melatonin is a member of the foremost hormones secreted by the pineal gland with numerous pharmacological properties in quite a number of diseases. However, its potential roles and possible mechanisms in ethanol-induced ferroptosis are still not clear completely. Ethanol feeding studies were performed upon a chronic-plus-binge ethanol feeding protocol in C57BL/6 mice with or without intraperitoneal injection administration of melatonin. HepG2 cells and mice primary hepatocytes were subjected to investigation for ethanol and melatonin. The results showed that melatonin dramatically ameliorated liver injury and decreased ferroptosis makers induced by ethanol. Meanwhile, melatonin effectively reversed the circadian misalignment caused by ethanol. Additionally, melatonin accelerated Nrf2 nuclear translocation and further activated its downstream anti-ferroptosis proteins including FTH, FPN, HO-1, and SLC7A11 in ethanol-changed mice liver tissues and HepG2 cells. However, the impact of melatonin on liver protection and anti-ferroptosis was offset upon brain and muscle ARNT-like 1 (BMAL1) knockdown with the notably blocked Nrf2-ARE pathway. Altogether, this study revealed that melatonin could alleviate ethanol-induced liver injury by impeding ferroptosis via reprogramming the circadian protein BMAL1 and subsequently activating the Nrf2-ARE anti-ferroptosis pathway. The emergence of novel liver protective effects and mechanism of melatonin on ethanol-induced ferroptosis may provide a new dimension for prevention or intervention against liver injury associated with ethanol.


Cell-free cloning and biolistic inoculation of an infectious cDNA of potato virus Y.
Potato virus Y (PVY) full-length cDNA has been found to be refractory to cloning in Escherichia coli cells. A full-length 9.7 kb PVY cDNA was obtained by reverse transcription polymerase chain reaction (RT-PCR) from the RNA of PVY (tuber necrotic strain, PVYNTN). Double-stranded DNA fragments were used as primers (ds megaprimers), to include signals for transcription in vivo (a cauliflower mosaic virus 35S RNA promoter and a nopaline synthase terminator) in the final PCR product. Biolistic bombardment with a helium particle gun was used to inoculate the amplified product to detached tobacco leaves. Inoculation of tobacco plants with ground inoculated leaves followed by northern blot, ELISA and immuno-electron microscopy demonstrated that the DNA was highly infectious with up to 90% of bombarded leaves containing the virus. This methodology will allow the use of reverse genetics in the study of PVY-plant interactions and will also be useful for obtaining infectious cDNA from other viruses with large RNA genomes.


Riedel's thyroiditis: treatment with tamoxifen.
Riedel's thyroiditis is an often disabling disease with clinical and histologic similarity to several other fibrous inflammatory disorders. Surgical treatment alone is often unsatisfactory in permanently alleviating airway compression, dysphagia, neck immobility, pain, or chronic fatigue syndrome. Investigation of drugs shown to be of benefit in the treatment of related fibrous disorders in which hormonal factors or inflammatory deregulation appear to be important is indicated. Tamoxifen has not been previously used in the treatment of Riedel's thyroiditis. Four patients with clinical and histologic diagnoses of Riedel's thyroiditis were evaluated before and after treatment with tamoxifen. Each had progressive symptomatic disease of 3 to 16 years' duration despite one or more surgical procedures and steroid therapy. Subjective improvement was noted in all cases, and objective changes were confirmed by periodic physical and computed tomographic examinations. Patients have been monitored for 1 to 4 years with subjective improvement in 100% and objective disease regression ranging from 50% to 100% in all patients. One patient had complete regression within 6 months, and another had more than 50% regression within 3 months. All have returned to predisease activity levels. There were no significant side effects of the therapy. Tamoxifen has proved to be the most effective drug therapy available for managing Riedel's thyroiditis. Our studies suggest that this is unrelated to antiestrogen activity. Tamoxifen's effectiveness may be caused by a mechanism by which it stimulates the release of transforming growth factor-beta, which may inhibit the fibroblastic proliferation characteristic of Riedel's thyroiditis.


Solvent density inhomogeneities and solvation free energies in supercritical diatomic fluids: a density functional approach.
Density functional theory is used to explore the solvation properties of a spherical solute immersed in a supercritical diatomic fluid. The solute is modeled as a hard core Yukawa particle surrounded by a diatomic Lennard-Jones fluid represented by two fused tangent spheres using an interaction site approximation. The authors' approach is particularly suitable for thoroughly exploring the effect of different interaction parameters, such as solute-solvent interaction strength and range, solvent-solvent long-range interactions, and particle size, on the local solvent structure and the solvation free energy under supercritical conditions. Their results indicate that the behavior of the local coordination number in homonuclear diatomic fluids follows trends similar to those reported in previous studies for monatomic fluids. The local density augmentation is particularly sensitive to changes in solute size and is affected to a lesser degree by variations in the solute-solvent interaction strength and range. The associated solvation free energies exhibit a nonmonotonous behavior as a function of density for systems with weak solute-solvent interactions. The authors' results suggest that solute-solvent interaction anisotropies have a major influence on the nature and extent of local solvent density inhomogeneities and on the value of the solvation free energies in supercritical solutions of heteronuclear molecules.


Functional annotation of the vlinc class of non-coding RNAs using systems biology approach.
Functionality of the non-coding transcripts encoded by the human genome is the coveted goal of the modern genomics research. While commonly relied on the classical methods of forward genetics, integration of different genomics datasets in a global Systems Biology fashion presents a more productive avenue of achieving this very complex aim. Here we report application of a Systems Biology-based approach to dissect functionality of a newly identified vast class of very long intergenic non-coding (vlinc) RNAs. Using highly quantitative FANTOM5 CAGE dataset, we show that these RNAs could be grouped into 1542 novel human genes based on analysis of insulators that we show here indeed function as genomic barrier elements. We show that vlinc RNAs genes likely function in cisto activate nearby genes. This effect while most pronounced in closely spaced vlinc RNA-gene pairs can be detected over relatively large genomic distances. Furthermore, we identified 101 vlinc RNA genes likely involved in early embryogenesis based on patterns of their expression and regulation. We also found another 109 such genes potentially involved in cellular functions also happening at early stages of development such as proliferation, migration and apoptosis. Overall, we show that Systems Biology-based methods have great promise for functional annotation of non-coding RNAs.


[Early respiratory support in anti-shock therapy of children with severe thermal trauma].
Search for effective method for decreasing the mortality of children with severe thermal injuries and approaches to preventing and treating multiorgan dysfunction in severe thermal injury is a pressing problem of reanimatology. The majority of scientists consider disorders in the ventilation-perfusion function of the lungs the main factor in the pathogenesis of burn shock. Lung injury is most often the first manifestation of multiple organ dysfunction. The depth of disorders in the gas exchange function of the lungs clearly correlates with the severity of burn injury and the terms of the beginning of respiratory support. The severity of burn shock, preclinical diagnosis of acute respiratory distress syndrome and disseminated intravascular blood coagulation, depth of hemodynamic disorders and disorders in the oxygen transporting system can serve as a criterion of the compensatory stress and be an indication for active respiratory therapy. Comparison of the main and control groups demonstrated the efficiency of early respiratory therapy in children with severe burns, because such therapy normalizes the blood oxygen transporting function and hemodynamic parameters sooner and with less strain for the compensatory potential of the organism.


Cerebral oxygenation following decompressive hemicraniectomy for the treatment of refractory intracranial hypertension.
Medically intractable intracranial hypertension is a major cause of morbidity and mortality after severe brain injury. One potential treatment for intracranial hypertension is decompressive hemicraniectomy (DCH). Whether and when to use DCH, however, remain unclear. The authors therefore studied the effects of DCH on cerebral O2 to develop a better understanding of the effects of this treatment on the recovery from injury and disease. The study focused on seven patients (mean age 30.6 +/- 9.7 years) admitted to the hospital after traumatic brain injury (five patients) or subarachnoid hemorrhage (two patients) as part of a prospective observational database at a Level I trauma center. At admission the Glasgow Coma Scale (GCS) score was 6 or less in all patients. Patients received continuous monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), blood pressure, and arterial O2 saturation. Cerebral oxygenation was measured using the commercially available Licox Brain Tissue Oxygen Monitoring System manufactured by Integra NeuroSciences. A DCH was performed when the patient's ICP remained elevated despite maximal medical management. All patients tolerated DCH without complications. Before the operation, the mean ICP was elevated in all patients (26 +/- 4 mm Hg), despite maximal medical management. After surgery, there was an immediate and sustained decrease in ICP (19 +/- 11 mm Hg) and an increase in CPP (81 +/- 17 mm Hg). Following DCH, cerebral oxygenation improved from a mean of 21.2 +/- 13.8 mm Hg to 45.5 +/- 25.4 mm Hg, a 114.8% increase. The change in brain tissue O2 and the change in ICP after DCH demonstrated only a modest relationship (r2 = 0.3). These results indicate that the use of DCH in the treatment of severe brain injury is associated with a significant improvement in brain O2.


Blubber and buoyancy: monitoring the body condition of free-ranging seals using simple dive characteristics.
Elephant seals regularly perform dives during which they spend a large proportion of time drifting passively through the water column. The rate of vertical change in depth during these "drift" dives is largely a result of the proportion of lipid tissue in the body, with fatter seals having higher (more positive or less negative) drift rates compared with leaner seals. We examined the temporal changes in drift rates of 24 newly weaned southern elephant seal (Mirounga leonina) pups during their first trip to sea to determine if this easily recorded dive characteristic can be used to continuously monitor changes in body composition of seals throughout their foraging trips. All seals demonstrated a similar trend over time: drift rates were initially positive but decreased steadily over the first 30-50 days after departure (Phase 1), corresponding to seals becoming gradually less buoyant. Over the following approximately 100 days (Phase 2), drift rates again increased gradually, while during the last approximately 20-45 days (Phase 3) drift rates either remained constant or decreased slightly. The daily rate of change in drift rate was negatively related to the daily rate of horizontal displacement (daily travel rate), and daily travel rates of more than approximately 80 km were almost exclusively associated with negative changes in drift rate. We developed a mechanistic model based on body compositions and morphometrics measured in the field, published values for the density of seawater and various body components, and values of drag coefficients for objects of different shapes. We used this model to examine the theoretical relationships between drift rate and body composition and carried out a sensitivity analysis to quantify errors and biases caused by varying model parameters. While variations in seawater density and uncertainties in estimated body surface area and volume are unlikely to result in errors in estimated lipid content of more than +/-2.5%, variations in drag coefficient can lead to errors of >or =10%. Finally, we compared the lipid contents predicted by our model with the lipid contents measured using isotopically labelled water and found a strong positive correlation. The best-fitting model suggests that the drag coefficient of seals while drifting passively is between approximately 0.49 (roughly corresponding to a sphere-shaped object) and 0.69 (a prolate spheroid), and we were able to estimate relative lipid content to within approximately +/-2% lipid. Our results suggest that this simple method can be used to estimate the changes in lipid content of free-ranging seals while at sea and may help improve our understanding of the foraging strategies of these important marine predators.


Operationalizing the Student Electronic Portfolio for Doctoral Nursing Education.
There is an increasing trend toward use of the electronic portfolio (e-portfolio) in Doctor of Nursing Practice programs. E-portfolios can provide documentation of competencies and achievement of program outcomes while showcasing a holistic view of the student achievement. Implementation of the e-portfolio requires careful decision making concerning software selection, set-up, portfolio components, and evaluation. The purpose of this article is to describe the implementation of an e-portfolio in a Doctor of Nursing Practice program and provide lessons learned during the implementation stage.


Refractory focal segmental glomerulosclerosis in the adult: complete and sustained remissions of two episodes of nephrotic syndrome after a single dose of rituximab.
Rituximab therapy may achieve remission of proteinuria in children or adolescents with refractory focal segmental glomerulosclerosis (FSGS), but its effectiveness in adults is uncertain. We describe the case of a 22-year-old Caucasian woman with refractory FSGS that achieved complete and sustained remission of nephrotic syndrome (NS) with one single 375 mg/m(2) rituximab infusion. At 4 months after complete circulating B-cell depletion, proteinuria declined from 4.5 to 0.27 g/24 h and serum albumin normalised. Rituximab was well tolerated and allowed complete withdrawal of previous immunosuppression with steroids and azathioprine. The patient was in sustained remission up to month 32, when she experienced a relapse. A second infusion of rituximab (375 mg/m(2)) achieved prompt proteinuria reduction with no additional immunosuppressants. At 48 months after the initial treatment, this patient is in complete remission without any immunosuppression. This case suggests that rituximab, even a single dose, may safely promote NS remission in adults with refractory FSGS.


Effectiveness and implementation of enhanced recovery after surgery programmes: a rapid evidence synthesis.
To assess the evidence on the impact of enhanced recovery programmes for patients undergoing elective surgery in acute hospital settings in the UK. Rapid evidence synthesis. Eight databases were searched from 1990 to March 2013 without language restrictions. Relevant reports and guidelines, websites and reference lists of retrieved articles were scanned to identify additional studies. Systematic reviews, RCTs not included in the systematic reviews, economic evaluations and UK NHS cost analysis, implementation case studies and surveys of patient experience in a UK setting were eligible for inclusion. We assessed the impact of enhanced recovery programmes on health or cost-related outcomes, and assessed implementation case studies and patient experience in UK settings. Studies were quality assessed where appropriate using the Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects critical appraisal process. 17 systematic reviews and 12 additional RCTs were included. Ten relevant economic evaluations were included. No cost analysis studies were identified. Most of the evidence focused on colorectal surgery. 14 innovation case studies and 15 implementation case studies undertaken in National Health Service settings described factors critical to the success of an enhanced recovery programme. Evidence for colorectal surgery suggests that enhanced recovery programmes may reduce hospital stays by 0.5-3.5 days compared with conventional care. There were no significant differences in reported readmission rates. Other surgical specialties showed greater variation in reductions in length of stay reflecting the limited evidence identified. Findings relating to other outcomes were hampered by a lack of robust evidence and poor reporting. There is consistent, albeit limited, evidence that enhanced recovery programmes can reduce length of patient hospital stay without increasing readmission rates. The extent to which managers and clinicians considering implementing enhanced recovery programmes in UK settings can realise savings will depend on length of stay achieved under their existing care pathway.


Elderly HIV-positive women: A gender-based analysis from the Multicenter Italian "GEPPO" Cohort.
HIV-positive patients are facing age-and disease-related comorbidities. Since gender differences in viro-immunological, clinical and therapeutic features have been described, aim of this analysis was to explore such differences in elderly HIV-positive females compared to males coming from the same cohort. Cross-sectional study. Ten Infectious Diseases Center participating to a new multicenter Italian geriatric Cohort aiming at describing health transition over time in HIV-positive individuals. HIV-positive patients aged ≥65 years old. We recorded clinical, viro-immunological and therapeutical data. We included 210 women (17%) out of 1237 patients. Compared to males, elderly females were less likely to present a HIV-RNA <50 copies/mL (74.3% vs. 81.8%, OR 0.64, 95%CI 0.44-0.93); they showed higher CD4+/CD8+ ratio (p = 0.016). Combined antiretroviral therapy (cART) strategies were similar between genders (p>0.05), although women were less likely to be treated with protease Inhibitors (PIs) (p = 0.05); specifically, in triple-drug regimens females received less PIs (28% vs 38% p = 0.022) and more integrase inhibitors (30% vs. 20% p = 0.012). Bone disease was more common in females (p<0.001) while males presented more frequently cardiovascular disease (CVD) (p<0.001). In females with bone disease, PIs and boosted regimens (38% vs. 53.7% p = 0.026 and 30.4 vs 44.0% p = 0.048 respectively) were prescribed less frequently. Polypharmacy was common and similar in both genders (20% vs. 22.8%, p = >0.05). A higher use of lipid-lowering drugs (20.5% vs. 14.8%, p = 0.04) was observed in females and yet they were less likely to receive anti-thrombotic agents (18.6% vs. 26.3%, p = 0.019) even when CVD was recorded (57.1% vs. 83.1%, p = 0.018). In multivariate analysis, we found that female gender was independently associated with a higher CD4+/CD8+ ratio but not with virological suppression. Elderly HIV-positive women display a worse virologic response despite a better immune reconstitution compared to males. The burden of comorbidities as well as the medications received (including cART) may slightly differ according to gender. Our data suggest that more efforts and focused interventions are needed in this population.


Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis.
According to strict clinical, hematological and morphological criteria, the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myeloid (megakaryocytic/granulocytic) metaplasia (AMM) or idiopathic myelofibrosis (IMF) are three distinct disease entities with regard to clinical manifestations, natural history and outcome in terms of life expectancy. As clonality studies have clearly demonstrated that fibroblast proliferation in AMM, as well as in many other conditions such as advanced stages of Ph(+)-essential thrombocythemia, Ph(+)-granulocytic leukemia, and Ph(-)-polycythemia vera, is polyclonal indicating that myelofibrosis is secondary to the megakaryocytic granulocytic metaplasia in these various conditions, AMM is illogically labeled as IMF. As abnormal megakaryocytic granulocytic metaplasia is the essential feature preceding the early prefibrotic stage of AMM, the term essential megakaryocytic granulocytic metaplasia (EMGM) can readily be used to characterize this condition more appropriately at the biological level. Clinical, hematological and morphological characteristics, in particular megakaryocytopoiesis and bone marrow cellularity, reveal diagnostic features, which enable a clear-cut distinction between ET, PV and EMGM or classical IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or only slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. EMGM, including the early prefibrotic stages as well as the various myelofibrotic stages of classical IMF appear to be a distinct neoplastic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. The histopathology of the bone marrow in prefibrotic EMGM and in classical IMF is dominated by atypical, enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis in ET, PV and EMGM is graded into: no reticulin fibrosis (MF0), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor or moderate collagen fibrosis (MF2) and advanced collagen fibrosis with osteosclerosis (MF3). Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis may be present in a minority of PV-patients at diagnosis and usually becomes apparent during long-term follow-up in the majority of PV-patients. Myelofibrosis secondary to the abnormal megakaryocytic and granulocytic myeloproliferation constitutes a prominent feature in the majority of EMGM/IMF at time of diagnosis and usually progresses more or less rapidly during the natural history of the disease. Life expectancy is normal in ET, normal during the 1st ten years and compromised during the 2nd ten years follow-up in PV, but significantly shortened in the prefibrotic stage of EMGM as well as in the various myelosclerotic stages of classical IMF. First line treatment options in prospective randomized clinical trials of newly diagnosed MPD-patients are control of platelet function with low-dose aspirin versus reduction of platelet count with anagrelide, interferon or hydroxyurea in ET; control of platelet and erythrocyte counts by interferon alone versus bloodletting plus hydroxyurea on indication in PV; interferon versus no treatment in the early stages of EMGM; a wait and see strategy in the fibrotic stages of EMGM or classical IMF with favorable prognostic factors, and bone marrow transplantation in classical IMF with poor prognostic factors at presentation or during short-term follow-up.


Anal Canal Duplication Associated with Presacral Cyst in an Adult.
Anal canal duplication (ACD) is a rare congenital malformation, usually detected early in life. We report a case of a 67-year-old female with symptomatic ACD associated with a presacral cyst. Physical examination revealed an accessory opening located in the midline, posterior to the true anus. Imaging examinations, including fistulography, endoanal ultrasonography, and magnetic resonance imaging, revealed a blind-ending fistulous tract without connecting with the rectum and a presacral cyst posterior to the rectum. Complete surgical excision of the tract with cyst was performed through a posterior sagittal approach. Histologic examination revealed squamous epithelium lining and smooth muscle bundles, thereby confirming ACD. The postoperative course was uneventful, and the patient was doing well; no recurrence was observed 4 years after surgery. ACD can present for the first time in infants, children, and adults. Imaging examinations are useful for the diagnosis and preoperative assessment of ACD. Therefore, ACD should be considered in the differential diagnosis, even in adults, when a posterior perineal orifice is encountered, particularly in female patients. Once ACD is suspected, intense imaging inspection is recommended to visualize the ACD and associated anomalies, and surgical removal is warranted to prevent inflammatory complications or malignant changes.


Causal role of Helicobacter pylori infection in gastric cancer: an Asian enigma.
Helicobacter pylori (H pylori) has been etiologically linked to gastric cancer.H pylori infection is more frequent in less developed Asian countries like India, Bangladesh, Pakistan,and Thailand and is acquired at early age than in more developed Asian countries like Japan and China. Frequency of gastric cancer, however, is very low in India, Bangladesh, Pakistan and Thailand compared to that in Japan and China. Similar enigma has been reported from Africa as compared to the West. Seroprevalence of H pylori infection in adult populations of India, Bangladesh, Pakistan and Thailand varies from 55% to 92%. In contrast, seroprevalence of H pylori in Chinese and Japanese adults is 44% and 55%,respectively. Annual incidence rate of gastric cancer in India, Bangladesh, and Thailand is 10.6, 1.3, 7.1 per 100,000 populations, respectively; in contrast, that in China and Japan is 32-59 and 80-115 per 100,000 populations, respectively. Several studies from India failed to show higher frequency of H pylori infection in patients with gastric cancer than controls. Available evidences did not support difference in H pylori strains as an explanation for this enigma. Despite established etiological role of H pylori, situation is somewhat enigmatic in Asian countries because in countries with higher frequency of infection,there is lower rate of gastric cancer. Host's genetic make-up and dietary and environmental factors might explain this enigma. Studies are urgently needed to solve this issue.


Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus.
The response to shunt surgery for idiopathic normal-pressure hydrocephalus (INPH) is variable because INPH is difficult to distinguish from other conditions causing the same symptoms. To date, no clinical picture or diagnostic test can distinguish INPH or predict response to cerebrospinal fluid (CSF) shunt surgery. We reviewed our 10-year experience with INPH to characterize long-term outcome and to identify independent predictors of outcome after shunt surgery. Patients were classified as having INPH only if they had: 1) ventriculomegaly, 2) two or more INPH clinical features, 3) no risk factor for secondary normal-pressure hydrocephalus, 4) A- or B-waves on CSF pressure monitoring, and 5) clinical improvement during a 3-day CSF drainage trial via a spinal catheter. Independent predictors of outcome were assessed via a multivariate proportional hazards regression analysis. One hundred thirty-two patients underwent 179 shunt surgeries. Forty-four (33%), 79 (60%), and 99 (75%) patients demonstrated objective improvement 3, 6, and 24 months after shunt surgery, respectively. Gait improved first in 88 (93%) patients. Dementia and urinary incontinence were twofold less likely to improve. Radiological evidence of corpus callosum distension, gait impairment as the primary symptom, and shorter duration of INPH symptoms predicted improvement. Duration of symptoms and gait as the primary symptom were independent predictors by multivariate analysis. INPH can be diagnosed accurately with CSF pressure monitoring and CSF drainage via a spinal catheter. CSF shunting is safe and effective for INPH with a long-term shunt response rate of 75%. Independent predictors of improvement are the presence of gait impairment as the dominant symptom and shorter duration of symptoms.


CD4+ T helper cell responses against human bocavirus viral protein 2 viruslike particles in healthy adults.
Human bocavirus (HBoV) was recently described as a new member of the Parvoviridae family, and its possible association with respiratory illness in infants has been discussed. To date, HBoV genomes have been detected worldwide in respiratory tract samples obtained from children with pulmonary diseases, whereas only limited data on virus-specific immunity are available, mainly because of the lack of recombinant viral antigens. HBoV viruslike particles (VLPs) were produced in insect cells and characterized by electron microscopy and cesium chloride gradient centrifugation. HBoV viral protein 2 (VP2)-specific antibodies and CD4+ T helper cell responses were analyzed by enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. VP2 capsid proteins of HBoV were produced in insect cells infected with a recombinant baculovirus, and the formation of icosahedral VLPs (diameter, 21-25 nm; sedimentation density, 1.33 g/cm(3)) was demonstrated. A significant increase in secretion of VP2-specific interferon-gamma was detected in cultures of peripheral blood mononuclear cells obtained from 69 healthy adults found to be positive for HBoV-specific immunoglobulin G antibodies, compared with control stimulations. In parallel, T cell responses against identically expressed parvovirus B19 VP2 VLPs were frequently observed in the individuals studied, without there being obvious cross-reactions between HBoV and parvovirus B19. Data suggest the presence of HBoV-specific immune responses in adults and strongly support a high prevalence of HBoV among humans.


Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.
The Raf/MEK/ERK (mitogen activated protein kinase-MAPK) signal transduction cascade is an important mediator of a number of cellular fates, including growth, proliferation, and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. The aim of this study was to elucidate a possible function of BRAF in liver tumours. Mutations of BRAF and KRAS were evaluated in 25 hepatocellular carcinomas (HCC) and in 69 cholangiocarcinomas (CC) by direct DNA sequencing analyses after microdissection. The presence of active intermediates of the MAPK pathway was assessed immunohistochemically. The results obtained were correlated with histopathological variables and patient survival. Activating BRAF missense mutations were identified in 15/69 CC (22%) and in one case of tumour surrounding liver. KRAS mutations were found in 31 of 69 (45%) CC examined and in two cases of tumour surrounding non-neoplastic liver tissue. In HCC, neither BRAF nor KRAS mutations were detected. All 31 CC with KRAS mutations had an intact BRAF gene. We failed to observe a correlation between BRAF or KRAS mutations and histopathological factors or prognosis of patients. Our data indicate that BRAF gene mutations are a relatively common event in CC but not in HCC. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway, either by RAS or BRAF mutation, was detected in approximately 62% of all CC and is therefore one of the most frequent defects in cholangiocellular carcinogenesis.


Early and late interstitial pneumonia following human bone marrow transplantation.
Interstitial pneumonia is a major determinant of early and late morbidity and mortality following bone marrow transplantation. Among 952 patients receiving allogeneic marrow grafts in Seattle, 35% developed interstitial pneumonia within 100 days of transplant. Development of early cytomegalovirus (CMV) or idiopathic interstitial pneumonia was infrequent in patients with aplastic anemia prepared only with cyclophosphamide. Use of total body irradiation (TBI) in the transplant preparation, increasing patient age, pretransplant seropositivity for CMV antibody and post-transplant development of graft-versus-host disease (GVHD) all increased the risk of CMV pneumonia. Late interstitial pneumonia was studied in patients with chronic GVHD. Among 198 patients with extensive chronic GVHD, 31 episodes of interstitial pneumonia (seven idiopathic, six CMV, six pneumocystis, five miscellaneous and four unknown causes, and three varicella-zoster) were observed 3-24 months after transplant. In untreated patients with chronic GVHD, 15% developed late interstitial pneumonia. Patients with chronic GVHD who received prednisone +/- azathioprine as immunosuppressive therapy and trimethoprim sulfamethoxazole for infection prophylaxis had an 8% incidence of interstitial pneumonia. Patients with chronic GVHD given immunosuppressive treatment without trimethoprim sulfamethoxazole prophylaxis had a 28% incidence of interstitial pneumonia. Trimethoprim sulfamethoxazole significantly reduced the incidence of late interstitial pneumonia in patients with chronic GVHD (p = 0.001).


Increased CD200 expression in post-transplant lymphoproliferative disorders correlates with an increased frequency of FoxP3(+) regulatory T cells.
CD200 is a membrane protein with immunosuppressive function and is expressed in many hematopoietic neoplasms, including acute myeloid leukemia (AML), plasma cell myeloma (PCM), and B-cell lymphoproliferative disorders, but is mostly negative in diffuse large cell lymphoma (DLBCL). CD200 has been shown to be a poor prognostic marker in AML and PCM; in AML, its immunomodulatory effect was linked to its ability to induce FoxP3(+) regulatory T cells (Tregs). Post-transplant lymphoproliferative disorders (PTLDs) arise in the setting of immune dysregulation, and tumor-infiltrating T cells, including Tregs, have been shown to correlate with outcome in these disorders. Because there is no literature data and CD200 is a potentially useful diagnostic and prognostic marker, we studied the expression of CD200 in a series of 38 PTLDs by immunohistochemistry (ICH), and found that 23.7% PTLDs were CD200(+) and showed strong membrane and cytoplasmic positivity in the neoplastic cells. All CD200(+) monomorphic PTLDs were DLBCLs and the median FoxP3(+) Treg count/hpf was higher in CD200(+) than in CD200(-) PTLDs: 22.6 vs. 0.30 (p < 0.001). These results indicated that almost a quarter of PTLDs in our series are CD200(+) by IHC, and CD200 expression correlates with the frequency of immunosuppressive Tregs. This is novel data and supports a pathophysiologic link between CD200 activity and Tregs. In our series, the 5-year overall survival was shorter in CD200(+) PTLDs, compared to CD200(-) patients, although this difference did not reach statistical significance. In addition, we find a higher proportion of CD200(+) monomorphic PTLD-DLBCLs (31.0%), as compared to de novo DLBCLs (7-8%, as found here and in other studies). This may indicate differential expression of CD200 in B-cell lymphomas arising in the setting of immune dysregulation, and raises the possibility of anti-CD200 immunotherapy for these cases.


Development of an MRI-Guided Approach to Selective Internal Radiation Therapy Using Holmium-166 Microspheres.
Selective internal radiation therapy (SIRT) is a treatment modality for liver tumours during which radioactive microspheres are injected into the hepatic arterial tree. Holmium-166 (166Ho) microspheres used for SIRT can be visualized and quantified with MRI, potentially allowing for MRI guidance during SIRT. The purpose of this study was to investigate the MRI compatibility of two angiography catheters and a microcatheter typically used for SIRT, and to explore the detectability of 166Ho microspheres in a flow phantom using near real-time MRI. MR safety tests were performed at a 3 T MRI system according to American Society for Testing of Materials standard test methods. To assess the near real-time detectability of 166Ho microspheres, a flow phantom was placed in the MRI bore and perfused using a peristaltic pump, simulating the flow in the hepatic artery. Dynamic MR imaging was performed using a 2D FLASH sequence during injection of different concentrations of 166Ho microspheres. In the safety assessment, no significant heating (ΔTmax 0.7 °C) was found in any catheter, and no magnetic interaction was found in two out of three of the used catheters. Near real-time MRI visualization of 166Ho microsphere administration was feasible and depended on holmium concentration and vascular flow speed. Finally, we demonstrate preliminary imaging examples on the in vivo catheter visibility and near real-time imaging during 166Ho microsphere administration in an initial patient case treated with SIRT in a clinical 3 T MRI. These results support additional research to establish the feasibility and safety of this procedure in vivo and enable the further development of a personalized MRI-guided approach to SIRT.


Application of tungsten as a carbon sink for synthesis of large-domain uniform monolayer graphene free of bilayers/multilayers.
We have found that tungsten (W) foils can be used for controlling the carbon diffusion within copper (Cu) enclosures to synthesize large-domain bi-/multi-layer-free monolayer graphene via chemical vapor deposition. We have observed that bi-/multi-layer graphene that nucleate underneath the monolayer graphene can be selectively removed by a W foil placed inside of the Cu enclosure. Both X-ray photoelectron spectroscopy and X-ray diffraction reveal the formation of tungsten sub-carbide (W2C), suggesting the role of the W foil as a carbon sink that alters the carbon concentration inside of the enclosure. Consequently, the bi-/multi-layers appear to dissolve. Utilizing this selective removal process, we were able to demonstrate large-domain (>200 μm) monolayer graphene that is free of any bi-/multi-layers by using Cu double enclosures.


Asymptotic properties of discrete unitary transforms.
A method for studying the asymptotic behavior of discrete transformations is developed using numerical quadrature theory. This method allows a more convenient examination of the correlation properties of common unitary transforms for large block sizes. As a practical result of this method it is shown that the discrete cosine transform is asymptotically optimal for all finite-order Markov signals.


Reciprocal transplants demonstrate strong adaptive differentiation of the model organism Arabidopsis thaliana in its native range.
To quantify adaptive differentiation in the model plant Arabidopsis thaliana, we conducted reciprocal transplant experiments for five years between two European populations, one near the northern edge of the native range (Sweden) and one near the southern edge (Italy). We planted seeds (years 1-3) and seedlings (years 4-5), and estimated fitness as the number of fruits produced per seed or seedling planted. In eight of the 10 possible site × year comparisons, the fitness of the local population was significantly higher than that of the nonlocal population (3.1-22.2 times higher at the southern site, and 1.7-3.6 times higher at the northern site); in the remaining two comparisons no significant difference was recorded. At both sites, the local genotype had higher survival than the nonlocal genotype, and at the Italian site, the local genotype also had higher fecundity. Across years, the relative survival of the Italian genotype at the northern site decreased with decreasing winter soil temperature. The results provide evidence of strong adaptive differentiation between natural populations of A. thaliana and indicate that differences in tolerance to freezing contributed to fitness variation at the northern site. In ongoing work, we explore the functional and genetic basis of this adaptive differentiation.


Histone octamer instability under single molecule experiment conditions.
We have studied the sample concentration-dependent and external stress-dependent stability of native and reconstituted nucleosomal arrays. Whereas upon stretching a single chromatin fiber in a solution of very low chromatin concentration the statistical distribution of DNA length released upon nucleosome unfolding shows only one population centered around approximately 25 nm, in nucleosome stabilizing conditions a second population with average length of approximately 50 nm was observed. Using radioactively labeled histone H3 and H2B, we demonstrate that upon lowering the chromatin concentration to very low values, first the linker histones are released, followed by the H2A-H2B dimer, whereas the H3-H4 tetramer remains stably attached to DNA even at the lowest concentration studied. The nucleosomal arrays reconstituted on a 5 S rDNA tandem repeat exhibited similar behavior. This suggests that the 25-nm disruption length is a consequence of the histone H2A-H2B dimer dissociation from the histone octamer. In nucleosome stabilizing conditions, a full approximately 145 bp is constrained in the nucleosome. Our data demonstrate that the nucleosome stability and histone octamer integrity can be severely degraded in experiments where the sample concentration is low.


Intraoperative radiation therapy on pancreatic cancer patients: a review of the literature.
Pancreatic cancer is rarely curable, and the overall survival rate at 5 years is under 4%. This study aimed to assess the efficacy, effectiveness and safety of intraoperative radiation therapy (IORT) as treatment in pancreatic cancer, by means of a systematic review of the literature. We searched Pubmed from 1980 until 2010 by means of prospective randomized trials. The aim was to assess the potential impact of IORT on local control, quality of life and overall survival. The search was restricted to articles published in English. IORT offers the opportunity to administer high doses of irradiation to areas of neoplastic involvement while attempting simultaneously to spare normal tissues in the region from potentially damaging radiation exposure. However, the results were not in favour of IORT in the case of pancreatic cancer in locally advanced and metastatic stages. There is no clear evidence to indicate the IORT as more effective than other therapies in treating pancreatic cancer.


Retroperitoneal fibrosis.
Retroperitoneal fibrosis (RPF) is a rare disease that is marked by systemic inflammation and the development of a periaortic fibroinflammatory mass. The fibroinflammatory infiltration can encase the abdominal aorta, ureters, and other abdominal organs. The clinical presentation often includes constitutional symptoms, abdominal pain, and signs of renal insufficiency or renal failure related to ureteral obstruction. Less frequently, RPF may present with vascular complications, such as venous thrombosis or claudication. The idiopathic form of RPF is most common but secondary forms have been described and are associated with malignancy and a variety of different medications. The pathophysiology is uncertain, but RPF has been linked with periaortitis and IgG4-related disease. Treatment centers on the relief of symptoms and complications associated with mass effects. Corticosteroids and other immunosuppressant therapies can improve constitutional symptoms, reduce infiltrate mass, and achieve disease remission, but a chronic relapsing course is not uncommon.


RF Heating of Gold Cup and Conductive Plastic Electrodes during Simultaneous EEG and MRI.
To investigate the heating of EEG electrodes during magnetic resonance imaging (MRI) scans and to better understand the underlying physical mechanisms with a focus on the antenna effect. Gold cup and conductive plastic electrodes were placed on small watermelons with fiberoptic probes used to measure electrode temperature changes during a variety of 1.5T and 3T MRI scans. A subset of these experiments was repeated on a healthy human volunteer. The differences between gold and plastic electrodes did not appear to be practically significant. For both electrode types, we observed heating below 4°C for straight wires whose lengths were multiples of ½ the radiofrequency (RF) wavelength and stronger heating (over 15°C) for wire lengths that were odd multiples of ¼ RF wavelength, consistent with the antenna effect. The antenna effect, which has received little attention so far in the context of EEG-MRI safety, can play as significant a role as the loop effect (from electromagnetic induction) in the heating of EEG electrodes, and therefore wire lengths that are odd multiples of ¼ RF wavelength should be avoided. These results have important implications for the design of EEG electrodes and MRI studies as they help to minimize the risk to patients undergoing MRI with EEG electrodes in place.


[A case of metronomic chemotherapy as an alternative cancer therapy for palliation].
An 82-year-old woman underwent colostomy and standard chemotherapy using tegafur/uracil and calcium folinate under a diagnosis of colon cancer. Recurrence occurred, with pulmonary metastasis, hydroureter, and numbness in the low extremities. When admitted to our palliative care unit, she and her family wanted to have mild and minimally toxic chemotherapy. We initiated oral combination of UFT and cyclophosphamide metronomic chemotherapy. She was able to eat for more than 7 months. Her body weight was maintained, and tumor markers were kept suprressed until her death. This case suggests the usefulness of an oral anti-cancer drug low dose metronomic chemotherapy as an alternative cancer therapy in elderly cancer patients requiring palliation.


Preferences and Utilities for Health States after Treatment of Olfactory Groove Meningioma: Endoscopic versus Open.
Objectives The purpose of this study is to report health utility scores for patients with olfactory groove meningiomas (OGM) treated with either the standard transcranial approach, or the expanded endonasal endoscopic approach. Design The time trade-off technique was used to derive health utility scores. Setting Healthy individuals without skull base tumors were surveyed. Main Outcome Measures Participants reviewed and rated scenarios describing treatment (endoscopic, open, stereotactic radiation, watchful waiting), remission, recurrence, and complications associated with the management of OGMs. Results There were 51 participants. The endoscopic approach was associated with higher utility scores compared with an open craniotomy approach (0.88 vs. 0.74; p < 0.001) and watchful waiting (0.88 vs.0.74; p = 0.002). If recurrence occurred, revision endoscopic resection continued to have a higher utility score compared with revision open craniotomy (0.68; p = 0.008). On multivariate analysis, older individuals were more likely to opt for watchful waiting ( p = 0.001), whereas participants from higher income brackets were more likely to rate stereotactic radiosurgery with higher utility scores ( p = 0.017). Conclusion The endoscopic approach was associated with higher utility scores than craniotomy for primary and revision cases. The present utilities can be used for future cost-utility analyses.


miR-222 isoforms are differentially regulated by type-I interferon.
Endogenous microRNAs (miRNAs) often exist as multiple isoforms (known as "isomiRs") with predominant variation around their 3'-end. Increasing evidence suggests that different isomiRs of the same family can have diverse functional roles, as recently demonstrated with the example of miR-222-3p 3'-end variants. While isomiR levels from a same miRNA family can vary between tissues and cell types, change of templated isomiR stoichiometry to stimulation has not been reported to date. Relying on small RNA-sequencing analyses, we demonstrate here that miR-222-3p 3'-end variants >23 nt are specifically decreased upon interferon (IFN) β stimulation of human fibroblasts, while shorter isoforms are spared. This length-dependent dynamic regulation of long miR-222-3p 3'-isoforms and >40 other miRNA families was confirmed in human monocyte-derived dendritic cells following infection with Salmonella Typhimurium, underlining the breadth of 3'-length regulation by infection, beyond the example of miR-222-3p. We further show that stem-loop miRNA Taqman RT-qPCR exhibits selectivity between 3'-isoforms, according to their length, and that this can lead to misinterpretation of results when these isoforms are differentially regulated. Collectively, and to our knowledge, this work constitutes the first demonstration that the stoichiometry of highly abundant templated 3'-isoforms of a same miRNA family can be dynamically regulated by a stimulus. Given that such 3'-isomiRs can have different functions, our study underlines the need to consider isomiRs when investigating miRNA-based regulation.


Words as social tools: Language, sociality and inner grounding in abstract concepts.
The paper introduces a new perspective on abstract concepts (e.g. "freedom") and their associate words representation, the Words As social Tools (WAT) view. Traditional theories conceptualize language as a way to index referents, a shortcut to access meaning, or a way to access meaning through words associations. WAT goes beyond these theories by identifying additional functions of words and language: words are tools helping us to perform actions and change the state of our social environment, and language is a means to improve our thought abilities, to control our behavior and plays a predictive role, helping us to form categories. Most importantly, WAT proposes that language and sociality - along with interoceptive and metacognitive processes - are key for the grounding of abstract concepts (ACs) that are more complex, variable, and more detached from perceptual and motor experience than concrete concepts (CCs). We highlight four tenets of WAT and discuss each of them in light of recent evidence: a. acquisition: compared to concrete concepts, the acquisition of abstract concepts relies more on social and linguistic inputs; b. brain representation: abstract concepts recruit more linguistic and social brain areas; c. mouth activation: due to the relevance of language for representing them, abstract concepts activate more the oral motor system; d. linguistic variability: abstract concepts are more affected by differences between spoken languages. We discuss evidence supporting these four tenets of WAT, and its advantages and limitations compared to other views on abstract concepts. Finally, we outline a conceptual proposal that specifies how internal models supporting the representation and processing of ACs can be grounded on interoceptive, metacognitive, social, and linguistic experience.


Associations among behavioral and acute physiologic responses to lipopolysaccharide-induced clinical mastitis in lactating dairy cows.
To examine behavioral and physiologic effects of lipopolysaccharide (LPS)-induced mastitis in lactating dairy cows. 20 Holstein cows. Cows were assigned to 5 blocks (4 cows/block) on the basis of parity and number of days in lactation. Intramammary infusion and IV treatments were assigned in a 2 × 2 factorial arrangement. Cows within each block were assigned to receive intramammary infusion with 25 μg of LPS or sterile PBS solution 3 hours after milking, and treatment with flunixin meglumine or sterile PBS solution was administered IV 4 hours after intramammary infusion. Video monitoring was continuously performed during the study. LPS-infused cows spent less time during the first 12 hours after infusion lying, eating, and chewing cud, compared with results for PBS solution-infused cows. Behavioral responses were correlated with physiologic responses for the first 12 hours after intramammary infusion. Flunixin meglumine administration after intramammary infusion mitigated some behavioral and clinical systemic responses. Intramammary infusion of LPS caused changes in both behavioral and physiologic variables in lactating dairy cows. Time spent lying, eating, and chewing cud were negatively correlated with physiologic responses in cows. Evaluation of behavior patterns may provide an ancillary measure, along with evaluation of physiologic variables, for monitoring well-being, clinical responses, and recovery from acute clinical mastitis.


Ileal flows and apparent ileal digestibility of fatty acids in growing gilts fed flaxseed containing diets.
An experiment was conducted to quantify the ileal flow and apparent ileal digestibility (AID) of fatty acids (FA) in growing gilts fed corn, wheat, and soybean meal based diets without (CON) or with ground flaxseed (FS). A total of 20 healthy purebred Yorkshire female pigs, weighing approximately 25 kg BW, were allotted to 1 of 3 feeding regimens: R1 (n = 5 pigs), feeding a diet containing 10% FS between 25 and 50 kg BW and CON diet thereafter, R2 (n = 10 pigs), feeding CON diet between 25 and 85 kg BW and a diet containing 6% FS thereafter, and R3 (n = 5 pigs), feeding CON diet between 25 and 110 kg BW. Titanium dioxide was used as an indigestible marker to assess AID and ileal flows of crude fat and FA. At 110 kg BW, pigs were slaughtered and representative digesta samples were obtained from the distal ileum. Ileal flows and AID of crude fat and individual FA did not differ (P > 0.10) between R1 and R3, and therefore, results from these 2 feeding regimens were combined to give 2 dietary treatments (CON and FS). There were no treatment effects on AID of crude fat and the sum of all FA, SFA, or MUFA. However, the AID of individual SFA decreased with chain length (linear; P < 0.05) for both FS and CON. The AID of myristic acid (14:0), individual trans-18:1 FA (6t-8t-18:1 to 12t-18:1), myristoleic acid (9c-14:1), and palmitoleic acid (9c-16:1) were greater for CON than FS (P < 0.05) whereas no diet effect was observed for the AID of linoleic acid (18:2n-6; 80.2 and 86.1% for FS and CON, respectively) and α-linolenic acid (18:3n-3; 86.7 and 89.8% for FS and CON, respectively). Ileal flows of rumenic acid (9c11t-CLA), n-3 PUFA, and highly unsaturated FA (HUFA; arachidonic, eicosatrienoic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) exceeded their intakes, indicating net appearance of these FA in the upper gut of the pig. It remains to be determined whether enteric microbiota can elongate and desaturate 18:2n-6 and 18:3n-3 and isomerize 18:2n-6. The contribution of endogenous FA losses from the host to the ileal flow of these FA should also be considered. Further studies are needed to quantify production of CLA isomers and PUFA in the small intestine of pigs, specifically the n-3 HUFA, and to assess their contribution to the FA supply of the host.


[Plasmodium falciparum Malaria and Exchange Transfusion Application].
Malaria caused by P. falciparum, is endemic in tropical and subtropical areas but is seen as sporadic cases in our country. A patient, early diagnosed and succesfully treated with antimalarial drug administration and a patient, with severe clinical manifestations and succesfully treated with antimalarial medication as well as Erythrocyte Exchange Transfusion (EET), who were not applied chemoprophylaxis are presented. The cases are presented in order to emphasize on the necessity of giving education to the people going to endemic areas from our country for work or travel and on the necessity of taking chemoprophylaxis and to take attention that EET may be preffered in the therapy of severe malaria cases.


Visual and modular detection of pathogen nucleic acids with enzyme-DNA molecular complexes.
Rapid, visual detection of pathogen nucleic acids has broad applications in infection management. Here we present a modular detection platform, termed enzyme-assisted nanocomplexes for visual identification of nucleic acids (enVision). The system consists of an integrated circuit of enzyme-DNA nanostructures, which function as independent recognition and signaling elements, for direct and versatile detection of pathogen nucleic acids from infected cells. The built-in enzymatic cascades produce a rapid color readout for the naked eye; the assay is thus fast (<2 h), sensitive (<10 amol), and readily quantified with smartphones. When implemented on a configurable microfluidic platform, the technology demonstrates superior programmability to perform versatile computations, for detecting diverse pathogen targets and their virus-host genome integration loci. We further design the enVision platform for molecular-typing of infections in patient endocervical samples. The technology not only improves the clinical inter-subtype differentiation, but also expands the intra-subtype coverage to identify previously undetectable infections.


Antibody to purified human colony-stimulating factor: use in the identification and isolation of granulocyte macrophage progenitor cells.
Conditioned media prepared from human lung, placenta, peripheral leukocytes, cultured human pancreatic carcinoma cells, and cultured cervical carcinoma cells exhibit a common pattern of two distinct types of colony-stimulating factors (CSF) separable by isoelectrofocusing. Type I and type II CSF differ in MW, isoelectric point, CFU-C specificity, and the morphologic type of colonies they stimulate. Type I CSF exhibits higher activity in mouse than in human marrow while type II is more active in human marrow. Type I and II CSF from cultured human pancreatic carcinoma have been purified, type I to apparent homogeneity, and antibody has been prepared against them in rabbits. We have utilized purified CSF and anti-CSF antibodies to label CFU-C fluorescently for the purpose of cell sorting via flow photometry. Human bone marrow cells preincubated with CSF and then treated first with anti-CSF antibody then fluorescein-labeled goat antirabbit globulin retain their ability to grow and form aggregates in the presence of additional CSF. Colonies thus formed exhibit fluorescence, the intensity of which diminishes with increase in aggregate size. These observations provide new insight into the biology of CFU-C and suggest the following: (1) Incubation of marrow cells with CSF for 2 h results in binding of CSF or an antigenic component of CSF to membranes of CFU-C. (2) Bound CSF-anti CSF complex remains on CFU-C membranes through at least 5-6 cell divisions. (3) The approach described offers great potential for the preparation of highly purified CFU-C populations by fluorescence cell sorting.


Mining the Human Tissue Proteome for Protein Citrullination.
Citrullination is a posttranslational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations, and while the modification has been linked to several diseases, including rheumatoid arthritis (RA) and cancer, its physiological or pathophysiological roles remain largely unclear. In part, this is owing to limitations in available methodology to robustly enrich, detect, and localize the modification. As a result, only a few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass-spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of ∼70 million tandem mass spectra yielded ∼13,000 candidate spectra, which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized ∼2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new, and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in the brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes. Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins, arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination.


Parent artery reconstruction for large or giant cerebral aneurysms using a Tubridge flow diverter (PARAT): study protocol for a multicenter, randomized, controlled clinical trial.
The treatment of large (10-25 mm) or giant (≥25 mm) cerebral aneurysms remains technically challenging, with a much higher complication and recanalization rate than that is observed for smaller aneurysms. The use of a flow diverter seems to facilitate the treatment of this special entity. In a previous single-center prospective study approved by the Ethics Committee and China Food and Drug Administration (CFDA), we obtained promising results, showing remarkable safety and effectiveness for the Tubridge flow diverter. Nevertheless, the previous study may have been limited by biases due to its single-center design and limited number of subjects. Furthermore, although various articles have reported durable results from treating aneurysms using flow diverters, increasing questions have arisen about this form of treatment. Thus, prospective, multiple-center, randomized trials containing more subjects are needed. This study is a multicenter, randomized, controlled clinical trial comparing clinical outcomes for patients with unruptured large/giant intracranial aneurysms treated with either conventional stent-assisted coiling or flow diverter implantation. A total of 124 patients who fulfill the inclusion and exclusion criteria will be randomized into either a treatment group or a control group in the ratio of 1:1. The treatment group will receive Tubridge implantation alone or combined with bared coils, and the control group will be treated with stent-assisted coiling (bare coils). The primary endpoint will be the complete occlusion rate at 6-month follow-up. Secondary endpoints include the immediate technique success rate, overall mortality, adverse events (ischemic stroke or intracranial bleeding) within 30 days, 90 days and 1 year post-operation, and the rate of intra-stent stenosis and thrombosis 6 months post-operation. This prospective trial may provide more information on the safety and efficacy of the Tubridge flow diverter and may potentially change the strategy for treatment of large or giant aneurysms. The trial is registered on the Chinese Clinical Trial Registry: ChiCTR-TRC-13003127.


Concanavalin-A as a Model for Induction of Murine Autoimmune Hepatitis: Role of TNF-α and NF-κβ During The Acute Phase.
Autoimmune hepatitis (AIH) is a heterogeneous immune-mediated chronic liver disease affecting children and adults. It is important to rely on a specific animal model to study the hepatic changes and to evaluate the roles played by pro-inflammatory cytokines such as tumor necrosis factor alpha "TNF-α" and transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells "NF-κβ" in the pathogenesis and outcome of the disease. This will help to identify specific targets for treatment of AIH. This study aimed at evaluating Concanavalin-A (Con A) as a model for induction of AIH and assessing splenocytes' TNF-α and hepatocytes' NF-κβ levels at comparable durations after induction of hepatitis with Con A to evaluate the relationship between both factors. Materials and methods: A total of 130 outbreed CD1 mice were divided into group (1) which included 100 mice with induced AIH and group (2) included 30 normal mice as negative controls. Intra-peritoneal injection of Concanavalin-A was used to induce hepatitis. Hepatic injury was evaluated by the levels of liver enzymes, histopathological evidence for hepatic inflammatory infiltrate and/or apoptosis. Splenocytes and hepatocytes were cultured for assessment of TNF-α and NF-κβ levels, respectively. Results: Con A injection caused a significant elevation in ALT and AST levels, portal inflammatory infiltrate, remarkable hepatocytes degeneration and marked increase of TNF-α levels, particularly within 24 hours, but all returned to normal within 1 week. Administration of another dose of Con A resulted in sharp significant elevation of liver enzymes, inflammatory infiltrate and hepatocyte apoptosis after 24 hours and sustained till the end of the study. There was a significant increase in NF-κβ throughout most of the study duration following Con A injection as compared to that of normal mice. In conclusions, intra-peritoneal administration of Con A, particularly two doses, represents an efficient approach for induction of immune-mediated hepatitis. T-cells play a major role in AIH through release of TNF-α. Coincidently, hepatitis seems to be associated with elevation of NF-κβ to protect hepatocytes. Thus TNF-α and NF-κβ can represent targets for treatment of AIH either through inhibition or augmentation, respectively.


[First results of PET / CT-guided secondary lymph node surgery on patients with a PSA relapse after radical prostatectomy].
CT and MRT are not applicable for the early detection of lymph node (LN) recurrence in prostate cancer. The PET / CT ((11)C-, (18)F-choline) technique can detect lesions >or= 5 mm and allows their topographic localisation. We have analysed positive (11)C-choline PET / CT LN findings in the case of a PSA increase after radical prostatectomy (RPE) histologicaly and documented the developing of PSA. 8 patients with PSA relapse after RPE and lymphadenedtomy (LA) were diagnosed as having LNM by means of (11)C-choline PET / CT. Using PET / CT, metastasis suspicious and nearby LN were openly dissected. Histological and PET / CT results were compared and the postoperative PSA-development was examined. Of the metastasis suspicious LN (11) 9 were histologically reconfirmed. All additionally removed LN (12) were correct negative. LNM were mostly (7 of 9) located in the iliaca interna area and pararectal. 6 of 7 patients with histological metastasis detection showed a PSA response. 3 of 6 patients with single metastasis had complete PSA remission (< 0.01 ng / ml, maximum follow-up: 28 months) without adjuvant therapy. (11)C-choline PET / CT could detect LNM with high specificity in our collective. These often lie beyond standard LA area, where they were primarily only resected by use of extended or sentinel LA. Because 3 patients with single LNM reached a complete PSA remission (< 0.01 ng / ml) without adjuvant therapy, the selected collective seems to benefit from secondary LN surgery. Whether or not individual patients can be cured by this surgery has to be demonstrated in a longitudinal study. However, an optimal imaging and experience in LN surgery have to be assured.


Segment-specific modifications of a neuropeptide phenotype in embryonic neurons of the moth, Manduca sexta.
We have studied differences in the development of segmentally homologous neurons to identify factors that may regulate a neuropeptide phenotype. Bilaterally paired homologs of the peripheral neuron L1 were identified in the thoracic and abdominal segments in embryos of the moth Manduca: each bipolar neuron arises at a stereotyped location and, at 40% of embryogenesis, projects its major process within the transverse nerve of its own segment. Shortly after the initiation of axonogenesis (approximately 41%), L1 homologs in all but the prothoracic segment (T1) were labelled specifically by an antiserum to the molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (authentic FMRFamide). Levels of peptide-immunoreactivity (IR) were comparable in all such segmental homologs up to the approximately 60% stage of embryogenesis, whereupon two distinct levels of peptide IR were displayed: homologs in the three most rostral segments (T2, T3, and A1; [abdominal segment 1]) showed high levels and were called Type I L1 neurons; homologs in the more caudal segments (A2-A8) typically showed low levels of IR and were called Type II L1 neurons. This segment-specific difference represented mature differentiated states and was retained in postembryonic stages. Intracellular dye fills of embryonic L1 neurons revealed that the morphogenesis of the Type I and II L1 neuron homologs was similar until approximately 48% of embryogenesis; thereafter it differed in two salient ways: (1) the cell bodies of Type II L1 neurons migrated approximately 150 microns laterally from their point of origin, and (2) the distal processes of the Type II L1 neurons contacted the heart, whereas those of Type I L1 neurons did not. Ultrastructural studies of both mature and developing L1 homologs showed that the FMRFamide-like antigen(s) localized specifically to secretory granules. Further, whereas the secretory granules in segmental homologs appeared similar initially (i.e., at approximately 50% of development), following the establishment of segment-specific differences, secretory granules found in mature Type I and II L1 neurons were cell type-specific.


Balloon-expandable intracoronary stents in the adult dog.
We studied the acute and chronic biological reaction to balloon-expandable intracoronary stents in the adult dog. Twenty stainless steel stents were placed, by standard angioplasty techniques, into the left anterior descending, left main, or circumflex coronary arteries of 20 dogs. Angiography was performed at 1, 3, 6, and 12 months and animals were killed in groups of three at 1, 3, 8, and 32 weeks, for gross, light, and electronmicroscopic analysis. All dogs survived, all stents were patent, and there was no evidence of myocardial infarction, spasm, rupture, or aneurysm formation during follow-up (longest 18 months; average, 12 months). The stent was initially covered by a thin layer of thrombus that was replaced later by neointimal muscular proliferation that reached its maximal thickness by 8 weeks (p less than .01). This neointima gradually thinned as it became more sclerotic and less cellular. The stents were covered completely by immature endothelium by 1 week without loss of side branches. We conclude that balloon-expandable intraluminal stents can be safely placed percutaneously into normal canine coronary arteries. Because of rapid endothelialization high patency rates can be expected, thus offering promise for clinical applications in man.


Change challenges traditional hospital/medical staff relationship.
1980 brought medical staffs and hospitals into a dialog on a variety of legal, regulatory, and administrative issues. This article examines how these issues have affected the traditional hospital/medical staff relationship.


Clinical pain, abstraction, and self-control: being in pain makes it harder to see the forest for the trees and is associated with lower self-control.
Although abstract thinking is a fundamental dimension of human cognition, it has received scant attention in research on pain and cognition. We hypothesized that physical pain impairs abstraction, because when people experience pain at high intensity levels, attention becomes concretely focused on the self in the here and now, where little else matters than finding relief for the pain they are currently experiencing. We also examined the relationship between pain and self-control, predicting that pain would debilitate self-control. Abstraction and self-reported self-control were assessed in 109 patients with musculoskeletal pain. The influence of specific pain qualities, such as pain intensity, pain interference with daily activities, pain duration, and pain persistence, was examined. Furthermore, we assessed other factors (e.g., anxiety, depression, and fatigue) that could be assumed to play a role in the pain experience and in cognitive performance. Higher pain intensity and persistence were associated with less abstract thinking. Furthermore, self-control decreased with greater pain intensity, persistence, and self-reported pain interference with daily activities. Self-reported depressive symptoms mediated the overall relationship between pain and self-control. Abstraction is compromised in patients reporting higher pain intensity and persistence. Different dimensions of pain also predict lower self-control although depression seems to account for the relationship between overall pain and self-control. The current study is the first to report an association between clinical musculoskeletal pain and abstraction. The results suggest that pain patients may suffer from a broader range of cognitive disadvantages than previously believed.


The photochemical activities and electron carriers of developing barley leaves.
The development of photochemical activities in isolated barley plastids during illumination of dark-grown plants has been studied and compared with the behaviour of plastocyanin, cytochromes f, b-559(LP), b-563 and b-559(HP) and pigments P546 (C550) and P700. Electron-transport activity dependent on Photosystem 1 and cyclic photophosphorylation dependent on N-methylphenazonium methosulphate (phenazine methosulphate) were very active relative to the chlorophyll content after only a few minutes of illumination of etiolated leaves, and then rapidly declined during the first few hours of greening. By contrast, Photosystem 2 activity (measured with ferricyanide as electron acceptor) and non-cyclic photophosphorylation were not detectable during the first 2(1/2)h of greening, but then increased in total amount in parallel with chlorophyll. The behaviour of the electron carriers suggested their association with either Photosystem 1 or 2 respectively. In the first group were plastocyanin, cytochrome f and cytochrome b-563, whose concentrations in the leaf did not change during greening, and cytochrome b-559(LP) whose concentration fell to one-half its original value, and in the second group were cytochrome b-559(HP) and pigment P546, the concentrations of which closely followed the activities of Photosystem 2. Pigment P700 could not be detected during the first hour, during which time some other form of chlorophyll may take its place in the reaction centre of Photosystem 1. The plastids started to develop grana at about the time that Photosystem 2 activity became detectable.


Epileptiform burst responses in ventral vs dorsal hippocampal slices.
Field potentials from area CA1 evoked by stimulation of the Schaffer collaterals were compared in dorsal and ventral hippocampal slices of rat brain. Responses were categorized into 5 response types on the basis of their morphology, ranging from simple (single spike component) to complex (multiple spike components). A higher percentage of ventral slices, compared to dorsal slices, responded with a complex morphology under normal and increased K+ concentrations. Thus, there was a significantly greater tendency for cells within the ventral hippocampus to generate burst responses.


Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry.
To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS). This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome. A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C). Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients.


[Assessment of endogenous thrombin potential and influence on it of different regimens of heparin therapy in patients with abdominal sepsis].
Abdominal sepsis (AS) is a systemic inflammatory reaction of organism in response to the development of infectious process in organs of the abdominal cavity. The course of AS is complicated by hypercoagulation syndrome which facilitates progression of endogenous intoxication. The investigation included 26 patients (14 men and 12 women, mean age 65.5 +/- 16.4 years) with AS. The test of thrombin generation (TTG) used in patients with AS allows assessment of changes in the hemostasis system and control of the heparin dose. It was established that TTG revealed elevated endogenous thrombin potential of blood practically in all patients with AS. In the patients given 25 000 IU of heparin the TTG indices showed a reliably decreased endogenous thrombin potential and peak thrombin concentration as compared with a group of patients given 10 000 IU of heparin.


Association of thiol/disulfide ratio with syntax score in patients with NSTEMI.
The aim of this study was to investigate the relation between native thiol/disulfide ratio (TDR) and severity of coronary atherosclerosis as assessed by the Syntax score (SXscore) in patients with non-ST elevation myocardial infarction (NSTEMI) who underwent coronary angiography. A total of 290 patients with NSTEMI who underwent coronary angiography, were included in the study between January and August 2014. Baseline coronary angiography determined the SXscore. The patients were divided into two groups: one with low SXscores (< 23) and the other with high SXscores (≥ 23). TDR was significantly lower in patients with high SXscores (p < 0.001). In-hospital mortality was higher in the group with low TDR and high SXscores. The cut-off value of TDR on admission that predicted a high SXscore in the groups combined was 14, with a sensitivity of 73% and a specificity of 68%. TDR can be determined by an easy, inexpensive, automated, or optionally manual spectrophotometric assay, and correlates inversely with SXscore in patients with NSTEMI.


Duration of hospitalization as a measure of cost on Children's Cancer Group acute lymphoblastic leukemia studies.
We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children's Cancer Group trials for acute lymphoblastic leukemia. The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.


[Capozide-50 alone and in combination with melatonin in therapy of hypertension].
Monotherapy with caposide-50 (C-50) was compared to combined therapy C-50 + melatonin in 22 patients with essential hypertension stage II (mean age 60 years). The patients were divided into two groups. Group 1 received C-50 at 8.00 a.m., group 2 received C-50 at 8.00 a.m. and melatonin at 10.00 p.m. in a dose 3 mg. Before the treatment and 14 days after it echo-CG was made to assess hemodynamics. Also, 24-h monitoring of arterial pressure was performed. The findings were analysed with variance statistics and cosinor-analysis. Group 1 achieved a moderate hypotensive effect. Circadian rhythm of systolic blood pressure was abnormal. Group 2 patients achieved more pronounced decline of systolic, diastolic and mean arterial pressures. Circadian rhythm of these pressure did not return to normal.


Dexamethasone regulates the program of secretory glycoprotein synthesis in hepatoma tissue culture cells.
The secretory glycoproteins synthesized by hepatoma tissue culture (HTC) cells were resolved by two-dimensional polyacrylamide gel electrophoresis of media from cells that were grown in the presence of [(3)H]fucose. These cells synthesize and secrete a complex set of fucose-containing glycoproteins. These secretory glycoproteins are distinct from those glycoproteins present in the plasma membrane of HTC cells. Incubation of HTC cells with dexamethasone has a pronounced effect on the quality and quantity (denoted here as the program) of secretory protein synthesis, as assayed by the short-term incorporation of labeled mannose, fucose, or methionine. The synthesis of two mannose- and fucose- containing glycoprotein series, one of 50,000 mol wt and a more heterogeneous series with mol wt of 35,000-50,000, is increased to a high level by the hormone; conversely, the synthesis of other secretory proteins, particularly one with mol wt of 70,000, is decreased or stopped completely. The synthesis of some major secretory proteins is not affected by the hormone. Dexamethasone has less of an effect on the composition of either total cell membrane glycoprotein or plasma membrane glycoprotein. But there is a decrease in the synthesis of a major membrane glycoprotein series with mol wt of 140,000. These effects of dexamethasone are relatively specific to HTC cells. Neither Reuber H-35 cells nor primary cultures of rat hepatocytes show the same response to the steroid. Two variant HTC cell lines, which were selected for their resistance to dexamethasone inhibition of extracellular plasminogen activator activity, respond only partially to the steroid-induced regulation of the secretory and membrane glycoproteins.