Influence of β-Lactam Infusion Strategy on Acute Kidney Injury.
Limited literature is available assessing nephrotoxicity with prolonged β-lactam infusions. This study compared the incidence of acute kidney injury (AKI) associated with a prolonged β-lactam infusion or an intermittent infusion. This was a retrospective, matched-cohort study at an academic medical center from July 2006 to September 2015. Adult patients who received piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) for at least 48 h were evaluated. Patients were excluded for preexisting renal dysfunction or pregnancy. The primary outcome was difference in incidence of AKI evaluated using the RIFLE (risk, injury, failure, loss, and end-stage) criteria. Patients in the intermittent group were matched 3:1 to patients in the prolonged-infusion group based on the following: β-lactam agent, age, gender, Charlson comorbidity index, baseline creatinine clearance, hypotension, receipt of vancomycin, and treatment in an intensive care unit. A total of 2,390 patients were included in the matched analysis, with 1,700 receiving intermittent infusions and 690 receiving prolonged infusion. The incidence of AKI was similar in the prolonged-infusion group to that in the intermittent-infusion group (21.6% versus 18.6%; P = 0.1). After multivariate regression, prolonged infusion was not associated with increased odds of AKI (odds ratio [OR], 1.07; 95% confidence interval [95% CI], 0.83 to 1.39). Independent predictors of AKI included TZP therapy, concomitant nephrotoxins, hypotension, and heart failure. Although AKIs were numerically more common in patients receiving prolonged β-lactam infusions than those receiving intermittent infusions, prolonged infusion was not an independent risk factor for AKI.


A novel organic mineral complex prevented high fat diet-induced hyperglycemia, endotoxemia, liver injury and endothelial dysfunction in young male Sprague-Dawley rats.
The prevalence of metabolic syndrome (MetSyn) has risen 35% since 2012 and over two-thirds of Americans exhibit features characterizing this condition (obesity, dyslipidemia, hyperglycemia, insulin resistance and/or endothelial dysfunction). The aim of this study was to evaluate the effects of a novel dietary supplemental organic mineral complex (OMC) on these risk factors in a rodent model of MetSyn. Six-week old male Sprague-Dawley rats were fed either standard chow or a high-fat diet (HFD) composed of 60% kcal from fat for 10 weeks. Rats were also treated with OMC in their drinking water at either 0 mg/mL (control), 0.6 mg/mL, or 3.0 mg/mL. The HFD-treated rats exhibited significantly increased body mass (p<0.05), epididymal fat pad mass (p<0.001), waist circumference (p = 0.010), in addition to elevations in plasma endotoxins (p<0.001), ALT activity (p<0.001), fasting serum glucose (p = 0.025) and insulin concentrations (p = 0.009). OMC did not affect body weight or adiposity induced by the HFD. At the higher dose OMC significantly blunted HFD-induced hyperglycemia (p = 0.021), whereas both low and high doses of OMC prevented HFD-induced endotoxemia (p = 0.002 and <0.001, respectively) and hepatocyte injury (ALT activity, p<0.01). Despite evidence of oxidative stress (elevated urinary H2O2 p = 0.032) in HFD-fed rats, OMC exhibited no demonstrable antioxidative effect. Consistent with prior studies, mesenteric arteries from HFD rats had more uncoupled eNOS (p = 0.006) and iNOS protein expression (p = 0.027) in addition to impaired endothelium-dependent vasodilation that was abrogated by the high dose of OMC (p<0.05). This effect of OMC may be attributed to the high nitrate content of the supplement. These findings suggest that the OMC supplement, particularly at the higher dose, ameliorated several risk factors associated with MetSyn via a non-antioxidant-dependent mechanism.


The Cryptococcus neoformans Rim101 transcription factor directly regulates genes required for adaptation to the host.
The Rim101 protein is a conserved pH-responsive transcription factor that mediates important interactions between several fungal pathogens and the infected host. In the human fungal pathogen Cryptococcus neoformans, the Rim101 protein retains conserved functions to allow the microorganism to respond to changes in pH and other host stresses. This coordinated cellular response enables this fungus to effectively evade the host immune response. Preliminary studies suggest that this conserved transcription factor is uniquely regulated in C. neoformans both by the canonical pH-sensing pathway and by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. Here we present comparative transcriptional data that demonstrate a strong concordance between the downstream effectors of PKA and Rim101. To define Rim101-dependent gene expression during a murine lung infection, we used nanoString profiling of lung tissue infected with a wild-type or rim101Δ mutant strain. In this setting, we demonstrated that Rim101 controls the expression of multiple cell wall-biosynthetic genes, likely explaining the enhanced immunogenicity of the rim101Δ mutant. Despite its divergent upstream regulation, the C. neoformans Rim101 protein recognizes a conserved DNA binding motif. Using these data, we identified direct targets of this transcription factor, including genes involved in cell wall regulation. Therefore, the Rim101 protein directly controls cell wall changes required for the adaptation of C. neoformans to its host environment. Moreover, we propose that integration of the cAMP/PKA and pH-sensing pathways allows C. neoformans to respond to a broad range of host-specific signals.


Isolation and characterization of Dam+ revertants and suppressor mutations that modify secondary phenotypes of dam-3 strains of Escherichia coli K-12.
Bacteria mutant in the dam (DNA adenine methylation) gene and in either recA or recB or recC genes are inviable (Virm- phenotype). From crosses between dam-3 bacteria and recA1 or recB21 recC22 strains, Vrm+ recombinants were recovered. Among these recombinants, Dam+ revertants were present which did not show the phenotypes normally associated with dam-3 bacteria. Three classes of indirectly suppressed strains (dam-3 genotype) were also recovered which showed alterations in the secondary phenotypes normally associated with dam-3 bacteria. These strains contained a second unlinked mutation in either mutL or mutS or sin. In addition, mutation in either sbcA or sbcB supresses the Vrm- phenotype of dam-3 recB21 recC22 strains.


The Werner syndrome helicase protein is required for cell proliferation, immortalization, and tumorigenesis in Scaffold attachment factor B1 deficient mice.
Werner syndrome (WS) is a rare disorder characterized by the premature onset of several pathologies associated with aging. The gene responsible for WS codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. We recently identified the Scaffold attachment factor B1 (SAFB1) as a potential interactants in human cells. SAFB1 is a multifunctional protein that binds both nucleic acids and is involved in the attachment of chromatin to the nuclear matrix, transcription, and stress response. Mice lacking SAFB1 exhibit developmental abnormalities in their lungs, high incidence of perinatal lethality, and adults develop different types of tumors. Mouse embryonic fibroblasts from Safb1-null animals are immortalized in culture. In this study, mice with a mutation in the helicase domain of the Wrn gene were crossed to Safb1-null mice. Double homozygous mutant mice exhibited increased apoptosis, a lower cell proliferation rate in their lungs and a higher incidence of perinatal death compared to Safb1-null mice. Few double homozygous mutants survived weaning and died before the age of six months. Finally, mouse embryonic fibroblasts lacking a functional Wrn helicase inhibited the immortalization of Safb1-null cells. These results indicate that an intact Wrn protein is required for immortalization and tumorigenesis in Safb1-null mice.


Effects of cocaine esterase following its repeated administration with cocaine in mice.
A bacterial cocaine esterase (CocE) produces robust protection and reversal of cocaine toxicity. The aim of this study was to investigate how effectiveness of CocE was changed following its repeated administration together with cocaine. Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality in mice. Immunologic responses of CocE were determined using ELISA. In the protection experiment, i.v. CocE 0.3mg was given 1min before a lethal dose of i.p. cocaine 180mg/kg. In the rescue experiment, i.v. CocE 0.3mg was given 1min after the occurrence of convulsions elicited by i.p. cocaine 100mg/kg. In both treatment paradigms, four trials were conducted in the same animals with a 2-week interval. CocE retained its effectiveness to protect or rescue mice during the first two trials and these mice did not show an immune response. In contrast, CocE's effectiveness was gradually reduced in the last two trials, accompanied by 10- and 100-fold increases in anti-CocE antibody titers. Nevertheless, effectiveness of CocE could be partially recovered by increasing the dose of CocE. In addition, escalating the dose of CocE from the minimum effective dose for repeated administration could also retain CocE's effectiveness longer and slow the production of anti-CocE antibodies. These results indicate that CocE is a weak antigen and it can maintain its protective and rescuing ability initially against cocaine-induced toxicity. Decreased effectiveness of CocE following repeated use can be partially improved by adjusting the dose and frequency of CocE treatment.


Increased interpretation of deep learning models using hierarchical cluster-based modelling.
Linear prediction models based on data with large inhomogeneity or abrupt non-linearities often perform poorly because relationships between groups in the data dominate the model. Given that the data is locally linear, this can be overcome by splitting the data into smaller clusters and creating a local model within each cluster. In this study, the previously published Hierarchical Cluster-based Partial Least Squares Regression (HC-PLSR) procedure was extended to deep learning, in order to increase the interpretability of the deep learning models through local modelling. Hierarchical Cluster-based Convolutional Neural Networks (HC-CNNs), Hierarchical Cluster-based Recurrent Neural Networks (HC-RNNs) and Hierarchical Cluster-based Support Vector Regression models (HC-SVRs) were implemented and tested on spectroscopic data consisting of Fourier Transform Infrared (FT-IR) measurements of raw material dry films, for prediction of average molecular weight during hydrolysis and a simulated data set constructed to contain three clusters of observations with different non-linear relationships between the independent variables and the response. HC-CNN, HC-RNN and HC-SVR outperformed HC-PLSR for the simulated data set, showing the disadvantage of PLSR for highly non-linear data, but for the FT-IR data set there was little to gain in prediction ability from using more complex models than HC-PLSR. Local modelling can ease the interpretation of deep learning models through highlighting differences in feature importance between different regions of the input or output space. Our results showed clear differences between the feature importance for the various local models, which demonstrate the advantages of a local modelling approach with regards to interpretation of deep learning models.


A Pilot Study of Exenatide Actions in Alzheimer's Disease.
Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD). We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD. Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone. Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs. The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.


Studies on the intestinal absorption characteristics of sulfasalazine, a breast cancer resistance protein (BCRP) substrate.
Oral sulfasalazine (SASP) is now used clinically as a probe substrate of a breast cancer resistance protein (BCRP) activity; however the intestinal absorption characteristics of SASP are not well understood. The purpose of this study was to clarify the characteristics of SASP transport in the mouse intestine. The everted ileum was incubated with SASP in the absence or presence of the Bcrp inhibitor Ko134. The steady-state intestinal absorptive clearance was 0.14 µL/min/cm in the absence of Ko134 and increased by 4.8-fold in the presence of Ko134. These results indicate that Bcrp mediates the efflux of SASP in the intestine. The absorptive clearance of SASP did not change in a concentration-dependent manner in the range of 0.1 to 50 µM in wild-type mice. By contrast, the absorptive clearance of SASP decreased significantly in a concentration-dependent manner in the presence of Ko134. Similar results were obtained in Bcrp(-/-) mice. These results suggest the possible involvement of some influx transporters in the intestinal absorption of SASP. In conclusion, both the influx and efflux transporters are involved in the intestinal absorption of SASP, which would explain why the absorptive clearance did not appear to change at various SASP concentrations in wild-type mice.


Antiphosphorylcholine antibody levels are elevated in humans with periodontal diseases.
Human immunoglobulin G2 (IgG2) serum concentrations and the IgG2 antibody response to Actinobacillus actinomycetemcomitans can be influenced by genes, by environmental factors such as smoking, and by periodontal disease status. Examination of the IgG2 response to phosphorylcholine (PC), a response thought to be mainly induced by the C polysaccharide of Streptococcus pneumoniae, suggested that periodontal disease status was also associated with this response. This prompted the hypothesis that PC is an important oral antigen associated with organisms in the periodontal flora and that anti-PC antibody is elevated as a consequence of periodontal disease. Subjects in various periodontal disease diagnostic categories in which attachment loss is exhibited were tested for anti-PC in serum. Those with adult periodontitis, localized juvenile periodontitis, generalized early-onset periodontitis, and gingival recession all had similar levels of anti-PC IgG2 serum antibody which were significantly greater than in the group of subjects with no attachment loss. Analysis of plaque samples from subgingival and supragingival sites in all diseases categories for reactivity with the anti-PC specific monoclonal antibody TEPC-15 revealed that a substantial proportion of the bacteria in dental plaque (30 to 40%) bear PC antigen; this antigen was not restricted to morphotypes resembling only cocci but was also present on rods and branched filamentous organisms. We found that S. mitis, S. oralis, and S. sanguis, as well as oral actinomycetes, including A. viscosus, A. odontolyticus, and A. israelii, incorporated substantial amounts of [(3)H]choline from culture media. Further analysis of antigens derived from these organisms by Western blot indicated that S. oralis, S. sanguis, A. viscosus, A. odontolyticus, and A. israelii contained TEPC-15-reactive antigens. The data show that many commonly occurring bacterial species found in dental plaque contain PC antigen and that immunization with plaque-derived PC antigens as a consequence of inflammation and periodontal attachment loss may influence systemic anti-PC antibody concentrations.


Effect of Potassium Permanganate as an Ethylene Scavenger and Physicochemical Characterization during the Shelf Life of Fresh Banana (Musa paradisiaca).
The conventional method of employing low temperatures for storage and distribution has long been the standard approach for preserving most fruits and vegetables. This practice is likewise prevalent in the retail industry, which relies on similar methods for transporting and maintaining the quality of perishable products on their shelves. The aim was to preserve bananas (Musa paradisiaca) using an ethylene scavenger, potassium permanganate, which is contained in small paper bags, to increase the storage and distribution time at low cost. The bananas were distributed in four plastic containers at a temperature of 23°C, three of the treatments contained different concentrations of potassium permanganate, and one was potassium permanganate free. The experimental period was 19 days, and the variations in weight loss, pH, titratable acidity, texture, color, and total soluble solids were analyzed. Potassium permanganate effectively reduced the changes in their physiological ripening.


Designing broad-spectrum anti-HIV-1 gRNAs to target patient-derived variants.
Clustered regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated protein 9 (Cas9), including specific guide RNAs (gRNAs), can excise integrated human immunodeficiency virus type 1 (HIV-1) provirus from host chromosomes. To date, anti-HIV-1 gRNAs have been designed to account for off-target activity, however, they seldom account for genetic variation in the HIV-1 genome within and between patients, which will be crucial for therapeutic application of this technology. This analysis tests the ability of published anti-HIV-1 gRNAs to cleave publicly available patient-derived HIV-1 sequences to inform gRNA design and provides basic computational tools to researchers in the field.


Type-specific contributions to chromosome size differences in Escherichia coli.
The Escherichia coli genome varies in size from 4.5 to 5.5 Mb. It is unclear whether this variation may be distributed finely throughout the genome or is concentrated at just a few chromosomal loci or on plasmids. Further, the functional correlates of size variation in different genome copies are largely unexplored. We carried out comparative macrorestriction mapping using rare-restriction-site alleles (made with the Tn10dRCP2 family of elements, containing the NotI, BlnI, I-CeuI, and ultra-rare-cutting I-SceI sites) among the chromosomes of laboratory E. coli K-12, newborn-sepsis-associated E. coli RS218, and uropathogenic E. coli J96. These comparisons showed just a few large accessory chromosomal segments accounting for nearly all strain-to-strain size differences. Of 10 sepsis-associated and urovirulence genes, previously isolated from the two pathogens by scoring for function, all were colocalized exclusively with one or more of the accessory chromosomal segments. The accessory chromosomal segments detected in the pathogenic strains from physical, macrorestriction comparisons may be a source of new virulence genes, not yet isolated by function.


Nitrogen oxide reactions in the urban plume of Boston.
The rate of removal or conversion of nitrogen oxides has been determined from airborne measurements in the urban plume of Boston. The average pseudo-first-order rate constant for removal was 0.18 per hour, with a range of 0.14 to 0.24 per hour under daylight conditions for four study days. The removal process is dominated by chemical conversion to nitric acid and organic nitrates. The removal rate suggests an atmospheric lifetime for nitrogen oxides of about 5 to 6 hours in urban air.


Radiation dose distributions in three dimensions from tomographic optical density scanning of polymer gels: II. Optical properties of the BANG polymer gel.
A newly developed method of radiation dosimetry makes use of the optical properties of polymer gels. The dose-response mechanism relies on the production of light-scattering polymer micro-particles in the gel at each site of radiation absorption. The scattering produces an attenuation of transmitted light intensity that is directly related to the dose and independent of dose rate. For the BANG polymer gel (bis, acrylamide, nitrogen, and gelatin) the shape of the dose-response curve depends on the fraction of the cross-linking monomer in the initial mixture and on the wavelength of light. At 500 nm the attenuation coefficient (mu) increases by approximately 0.7 mm-1 when the dose increases from 0 to 5 Gy. The refractive index of an irradiated gel shows no significant dispersion in the visible region and depends only slightly on the dose. Turbidity difference spectra are compared with theoretical spectra of efficiency factors for total scattering, derived using Mie-Debye theory, and the average sizes of the cross-linked particles produced by radiation, as a function of dose, are established. The particle sizes increase with dose and reach approximately the wavelength of red light. The dependence of the particle sizes on cross-linker fraction parallels a similar dependence of the water proton NMR transverse relaxation rate dose response.


Accurate forest projections require long-term wood decay experiments because plant trait effects change through time.
Whether global change will drive changing forests from net carbon (C) sinks to sources relates to how quickly deadwood decomposes. Because complete wood mineralization takes years, most experiments focus on how traits, environments and decomposer communities interact as wood decay begins. Few experiments last long enough to test whether drivers change with decay rates through time, with unknown consequences for scaling short-term results up to long-term forest ecosystem projections. Using a 7 year experiment that captured complete mineralization among 21 temperate tree species, we demonstrate that trait effects fade with advancing decay. However, wood density and vessel diameter, which may influence permeability, control how decay rates change through time. Denser wood loses mass more slowly at first but more quickly with advancing decay, which resolves ambiguity about the after-life consequences of this key plant functional trait by demonstrating that its effect on decay depends on experiment duration and sampling frequency. Only long-term data and a time-varying model yielded accurate predictions of both mass loss in a concurrent experiment and naturally recruited deadwood structure in a 32-year-old forest plot. Given the importance of forests in the carbon cycle, and the pivotal role for wood decay, accurate ecosystem projections are critical and they require experiments that go beyond enumerating potential mechanisms by identifying the temporal scale for their effects.


Molecular targets for nutrients involved with cancer prevention.
Dietary nutrients can influence cancer risk by inhibiting or enhancing carcinogenesis through diverse mechanisms of action. The identification and elucidation of their sites of action have been a focus of nutrition and cancer research for more than four decades. Transforming nutrition and cancer research from a predominantly observational to a molecular approach offers exciting opportunities for truly identifying those who will and will not benefit from dietary intervention strategies. The emerging field of nutritional genomics, defined here as the study of any genetic or epigenetic interaction with a nutrient, will be key to this evolution. Unraveling which genetic upregulation or downregulation leads to subsequent phenotype changes will not be easy. There is evidence that genetic polymorphisms can influence the dynamics between nutrients and molecular targets and, thus, contribute to variation in response among individuals. Because many molecular targets will likely be identified, it may be necessary to credential nutrients, that is, to determine which specific nutrient-related genetic and epigenetic changes bring about phenotypic changes, to establish which interactions are the most important and under what circumstances. Vitamin D, calcium, folate, selenium, genistein, and resveratrol are highlighted, because they represent specific classes of nutrients and illustrate the need to credential various nutrients to understand their physiological significance in cancer prevention. As the science of nutrition unfolds, a clearer understanding will emerge about how nutrients can modulate cancer risk through molecular interactions and how foods might be changed by agronomic approaches and/or biotechnology. Undeniably, embracing new genomic technologies offers exciting opportunities for advances in the broad area of nutrition, especially those related to cancer prevention.


Pain in Parkinson's disease.
Parkinson's disease is characterized primarily as a neurodegenerative disorder that leads to disabling motor and cognitive impairment. PD is less widely appreciated as a disease causing a substantial variety of pain syndromes, although the prevalence of pain in PD is approximately 40%. In a minority of patients, pain is so severe and intractable that it overshadows the motor symptoms of the disorder. In recent years, descriptive surveys of non-motor symptoms in PD have led to a classification of painful sensations into one or more of several categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, akathitic discomfort, and primary, central parkinsonian pain. A framework for diagnosing and treating painful PD is described in this review, together with recent insignts into the neurophysiological mechanisms and substrates of pain in PD.


Practical management of stress-related gastric ulcers.
Stress ulcers develop in patients who have been subjected to abnormally elevated levels of stress, especially stress caused by conditions associated with reduced gastric blood flow, such as major burns, hypovolemia, and sepsis. Since a significant, often fatal, upper gastrointestinal hemorrhage is a common sequela of stress ulcers, prevention of progression of the lesions is a sensible goal. In numerous clinical trials, antacids, H2-antagonists, and sucralfate have demonstrated comparable effectiveness in preventing bleeding and the associated life-threatening sequelae. The choice of the ideal agent depends on individual patient factors, concomitant disease states and drug therapy, administration requirements, nursing availability, potential adverse effects, and expense.


Assessing mobility difficulties for cross-national comparisons: results from the World Health Organization Study on Global AGEing and Adult Health.
To assess the correspondence between self-reported and measured indicators of mobility disability in older adults in six low- and middle-income countries (LMICs). Cross-sectional analysis of Study on Global AGEing and Adult Health (SAGE). Household surveys in China, India, Russia, South Africa, Ghana, and Mexico. Community-dwelling SAGE respondents aged 65 and older (N = 12,215). Objective mobility was assessed according to a 4-m timed walk at normal pace conducted in the respondent's home; slow walking speed was defined according to the Fried frailty criteria (lowest quintile of walking speed, adjusted for age and height). Self-reported mobility difficulty was assessed according to a question about ability to walk 1 km; this response was dichotomized into any versus no self-reported difficulty walking 1 km (reference no difficulty). The age- (5-year groups) and sex-specific probability of self-reporting difficulty walking 1 km was estimated in those with a measured slow walk using logistic regression. Between 42% and 76% of people aged 65 and older reported any difficulty walking 1 km. Average walking speed was slowest in Russia (0.61 m/s) and fastest in China (0.88 m/s). The probabilities of reporting any difficulty walking 1 km in women aged 65 to 69, for example, with a slow walk varied (China = 0.35, India = 0.90, Russia = 0.68, South Africa = 0.81, Ghana = 0.91, Mexico = 0.73; test of country differences P < .001). There was significant variation at older ages, albeit smaller in magnitude. Patterns were similar for men. Although correspondence between an objective and self-reported measure of mobility was generally high, correspondence differed significantly between LMICs. International comparisons of self-reported disability measures for clinical, prevention, and policy guidelines in LMICs should consider that self-reported data may not correspond to objective measures uniformly between countries.


Biochemistry and adaptive colouration of an exceptionally preserved juvenile fossil sea turtle.
The holotype (MHM-K2) of the Eocene cheloniine Tasbacka danica is arguably one of the best preserved juvenile fossil sea turtles on record. Notwithstanding compactional flattening, the specimen is virtually intact, comprising a fully articulated skeleton exposed in dorsal view. MHM-K2 also preserves, with great fidelity, soft tissue traces visible as a sharply delineated carbon film around the bones and marginal scutes along the edge of the carapace. Here we show that the extraordinary preservation of the type of T. danica goes beyond gross morphology to include ultrastructural details and labile molecular components of the once-living animal. Haemoglobin-derived compounds, eumelanic pigments and proteinaceous materials retaining the immunological characteristics of sauropsid-specific β-keratin and tropomyosin were detected in tissues containing remnant melanosomes and decayed keratin plates. The preserved organics represent condensed remains of the cornified epidermis and, likely also, deeper anatomical features, and provide direct chemical evidence that adaptive melanism - a biological means used by extant sea turtle hatchlings to elevate metabolic and growth rates - had evolved 54 million years ago.


[Morphologic indices of the rat heart after colchicine application to the vagus nerve].
By means of the light optic and electron microscopic methods atrial ganglia, myocytes, vessels of the right cardiac chambers have been studied in rats 2 days--3 weeks after application of 100 mcg of colchicine on the right nervus vagus. Certain changes of the neural fibers have been described at the area of the application. In the myocardium the microcirculatory bed, focal edema and hypoxic alterations of the myocyte ultrastructure have been revealed. In the ventrical ganglia destruction of some terminals of the preganglionar fibers, chromatolysis and vacuolization of single neurocytes, as well as intraganglionar granule-containing cells have been found. The changes described take place for 7 days and they nearly completely disappear in 10 days. A suggestion is made that some phenomena, in particular, destruction of the preganglionar fibers and changes of the cardiac microcirculatory bed are connected with certain disturbances of the quick transport of substances in the nervus vagus fibers.


Pituitary tumor-transforming 1 increases cell motility and promotes lymph node metastasis in esophageal squamous cell carcinoma.
Human pituitary tumor-transforming 1 (PTTG1)/securin is a putative oncoprotein that is overexpressed in various tumor types. However, the involvement of PTTG1 in gastrointestinal cancer development and progression remains unclear. In this study, we investigated the clinical significance and biological effects of PTTG1 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical studies performed on 113 primary ESCC specimens revealed a high prevalence of PTTG1 overexpression (60.2%), which was significantly associated with lymph node metastasis (regional, P = 0.042; distant, P = 0.005), advanced tumor stage (P = 0.028), and poorer overall survival (P = 0.017, log-rank test; P = 0.044, Cox proportional hazard model). Eleven ESCC cell lines expressed PTTG1 protein at levels 2.4 to 6.6 times higher than those in normal esophageal epithelial cells (HEEpiC). PTTG1 protein expression was confined to the nucleus in HEEpiC cells but present in both the cytoplasm and nucleus in ESCC cells. Two small interfering RNAs (siRNA) inhibited PTTG1 mRNA and protein expression in three ESCC cell lines by 77% to 97%. In addition, PTTG1 down-regulation by these siRNAs significantly reduced cell motility in all three ESCC cell lines (P < 0.01) in vitro, as well as popliteal lymph node metastases of ESCC cells in nude mice (P = 0.020). Global gene expression profiling suggested that several members of the Ras and Rho gene families, including RRAS, RHOG, ARHGAP1, and ARHGADIA, represented potential downstream genes in the PTTG1 pathway. Taken together, these findings suggest that PTTG1 overexpression promotes cell motility and lymph node metastasis in ESCC patients, leading to poorer survival. Thus, PTTG1 constitutes a potential biomarker and therapeutic target in ESCCs with lymph node metastases.


Metabolic consequences of submersion asphyxia in mammals and birds.
On submersion, the cardiovascular system of naturally diving animals is virtually transformed into a heart-brain-lung preparation as the result of intense and highly selective neurogenic vasoconstriction. A supply of oxygen from the circulating blood cells to the heart and the brain is thereby secured. Peripheral tissues, e.g. muscles and kidneys, have to depend on local stores of oxygen, i.e. myoglobin, or, when these are exhausted, on anaerobic metabolism. In spite of such physiological adjustments, however, arterial pO2 will inevitably decrease throughout the underwater episode. In prolonged dives values lower than 10mmHg can be observed. Moreover, the ischaemia in the peripheral tissues will, in some animals, e.g. arctic seals and whales, result in a profound decrease in the temperature of tissues such as the skin. The aim of the present report is to review some of the more important biochemical mechanisms that allow diving mammals and birds to cope with the above-mentioned combined asphyxic and temperature stresses for prolonged periods. Some of the osmotic problems arising from the rapid wash-out of acidic metabolic end products from the previously ischaemic tissues on emergence are also discussed.


'Mysterious' moose disease in Sweden. Similarities to copper deficiency and/or molybdenosis in cattle and sheep. Biochemical background of clinical signs and organ lesions.
The moose (Alces alces L.) in an acid rain affected region in south-west Sweden has developed a complex disease with numerous clinical signs, most of which are consistent with those of secondary copper (Cu) deficiency and/or molybdenosis in cattle and sheep. The clinical signs of the moose disease reported to date include diarrhoea, anorexia, emaciation, achromotrichia, alopecia, sudden heart failure and osteoporosis. Findings at necropsy included mucosal oedema, atrophied lymphoid tissues of the mucous membranes of the alimentary tract, neuropathy, neuronal degeneration and uni- or bilateral corneal opacity. In a study of clinically healthy animals from the affected region in Sweden over a 12-year period (1982-1994), the hepatic Cu concentration decreased by 50% and the liver and kidney cadmium (Cd) concentration decreased by 25-35%, while the molybdenum (Mo) concentration increased by 20-40%. These changes are probably related to an increase in the pH of the soil and water in the moose environment and a consequent change in the uptake of these elements by the plants consumed by the moose. It is noteworthy that the occurrence of the disease in the mid 1980s coincided with increased liming undertaken to counteract the noxious effects of acid rain in this region. Clinical signs and lesions of the moose disease resemble those reported for Cu deficiency and/or molybdenosis in cattle and sheep. To elucidate the complex, multi-faceted clinical signs of the moose disease, the clinical signs and necropsy findings are discussed in relation to the biochemical functions of certain well-known Cu-dependent enzymes, e.g. depigmentation of hair due to depressed tyrosinase activity, osteoporosis by depressed lysyl oxidase activity, sudden heart failure due to decreased activity of lysyl oxidase, cytochrome c oxidase and Cu/Zn-superoxide dismutase; in addition, mucosal lesions and ulcerations due to loss of activity of diamine oxidase as well as of lysyl oxidase and cytochrome c oxidase. It is concluded from the present findings that the moose disease is most probably a Cu deficiency and/or a molybdenosis-type syndrome.


Efficacy and safety of eperisone in patients with low back pain: a double blind randomized study.
Eperisone hydrochloride (4'-ethyl-2-methyl-3-piperidinopropiophenone hydrochloride) is an antispastic agent used for treatment of diseases characterized by muscle stiffness and pain. The aim of this research was to investigate the efficacy of eperisone in patients with acute low back pain and spasticity of spinal muscles. The study design was a randomized, double-blind (double-dummy) study in 160 patients with low back pain and no Rx finding of major spinal diseases, randomly assigned to a treatment with oral eperisone 100 mg three times daily (t.i.d.) or thiocolchicoside 8 mg twice daily (b.i.d.) for 12 consecutive days. Analgesic activity was evaluated by scoring "spontaneous pain" (VAS) and pain on movement and pression (4-digit scale), while muscle relaxant activity of the medication was evaluated by means of the "hand-to-floor" distance and the Lasegue's manoeuvre. All the measures were done at the inclusion day and after 3, 7 and 12 days of treatment. The two medications had comparable analgesic and muscle relaxant efficacy. Sponta-neous pain and pain on movement/pressure were significantly reduced by both treatments. Moreover, both eperisone- and thiocolchicoside-treated patients showed a clinically evident muscle relaxation as proved by a progressive reduction in the "hand-to-floor" distance and increase in the articular excursion (Lasegue's manoeuvre). Only 5% of eperisone-treated patients showed minor gastrointestinal side effects, while the incidence of side effects in the thiocolchicoside group was 21.25%. Moreover, in the thiocolchicoside-treated patients also diarrhoea was present, which reached a moderate intensity in some cases. In conclusions, eperisone represents a valuable and safer alternative to other muscle relaxant agents for treatment of low back pain.


Polyreactivity of antibodies from different B-cell subpopulations is determined by distinct sequence patterns of variable region.
An antibody molecule that can bind to multiple distinct antigens is defined as polyreactive. In the present study, we performed statistical analyses to assess sequence correlates of polyreactivity of >600 antibodies cloned from different B-cell types of healthy humans. The data revealed several sequence patterns of variable regions of heavy and light immunoglobulin chains that determine polyreactivity. The most prominent identified patterns were increased number of basic amino acid residues, reduced frequency of acidic residues, increased number of aromatic and hydrophobic residues, and longer length of CDR L1. Importantly, our study revealed that antibodies isolated from different B-cell populations used distinct sequence patterns (or combinations of them) for polyreactive antigen binding. Furthermore, we combined the data from sequence analyses with molecular modeling of selected polyreactive antibodies and demonstrated that human antibodies can use multiple pathways for achieving antigen-binding promiscuity. These data reconcile some contradictions in the literature regarding the determinants of antibody polyreactivity. Moreover, our study demonstrates that the mechanism of polyreactivity of antibodies evolves during immune response and might be tailored to specific functional properties of different B-cell compartments. Finally, these data can be of use for efforts in the development and engineering of therapeutic antibodies.


NMR identification of endogenous metabolites interacting with fatted and non-fatted human serum albumin in blood plasma: Fatty acids influence the HSA-metabolite interaction.
Metabolites and their concentrations are direct reporters on body biochemistry. Thanks to technical developments metabolic profiling of body fluids, such as blood plasma, by for instance NMR has in the past decade become increasingly accurate enabling successful clinical diagnostics. Human Serum Albumin (HSA) is the main plasma protein (∼60% of all plasma protein) and responsible for the transport of endogenous (e.g. fatty acids) and exogenous metabolites, which it achieves thanks to its multiple binding sites and its flexibility. HSA has been extensively studied with regard to its binding of drugs (exogenous metabolites), but only to a lesser extent with regard to its binding of endogenous (non-fatty acid) metabolites. To obtain correct NMR measured metabolic profiles of blood plasma and/or potentially extract information on HSA and fatty acids content, it is necessary to characterize these endogenous metabolite/plasma protein interactions. Here, we investigate these metabolite-HSA interactions in blood plasma and blood plasma mimics. The latter contain the roughly twenty metabolites routinely detected by NMR (also most abundant) in normal relative concentrations with fatted or non-fatted HSA added or not. First, we find that chemical shift changes are small and seen only for a few of the metabolites. In contrast, a significant number of the metabolites display reduced resonance integrals and reduced free concentrations in the presence of HSA or fatted HSA. For slow-exchange (or strong) interactions, NMR resonance integrals report the free metabolite concentration, while for fast exchange (weak binding) the chemical shift reports on the binding. Hence, these metabolites bind strongly to HSA and/or fatted HSA, but to a limited degree because for most metabolites their concentration is smaller than the HSA concentration. Most interestingly, fatty acids decrease the metabolite-HSA binding quite significantly for most of the interacting metabolites. We further find that competition between the metabolites for binding is absent for most of these metabolites. These mappings in plasma mimics may thus open new opportunities for improved metabolic profiling of blood plasma. For instance, correct metabolite concentrations can be determined for the non-interacting metabolites and/or concentration corrections made for interacting metabolites. Secondly, the interacting metabolites could be used to act as reporters on HSA and fatty acid concentration in plasma, and thus potentially act as biomarker in diagnostic studies of trauma or cardiovascular diseases. Finally, we find in the blood plasma mimics that after ultrafiltration, commonly used to remove the protein from plasma, the measured concentration equals the total metabolite concentration, except for the strongest binding metabolite citrate.


Variable phenotype of a null PPP1R13L allele in children with dilated cardiomyopathy.
Childhood-onset cardiomyopathy is a genetically heterogeneous group of conditions with several genes implicated. Recently, biallelic loss-of-function variants in PPP1R13L have been reported in association with a syndromic form of dilated cardiomyopathy (DCM). In addition, affected children manifest skin and hair abnormalities, cleft lip and palate (CLP), and eye findings. Here, we delineate the condition further by describing the phenotype associated with a homozygous frameshift variant (p.Arg330 ProfsTer76) in PPP1R13L detected in two sibships in a consanguineous family with six affected children. The index case had DCM and wooly hair, two of his siblings had DCM and CLP while three cousins had, in addition, glaucoma. Global developmental delay was observed in one child. All the children, except one, died during early childhood. Whole exome sequencing and whole genome sequencing did not reveal any other plausible variant. We provide further evidence that implicates PPP1R13L in a variable syndromic form of severe childhood-onset DCM and suggests expanding the spectrum of this condition to include glaucoma. Given the variability of the phenotype associated with PPP1R13-related DCM, a thorough evaluation of each case is highly recommended even in the presence of an apparently isolated DCM.


Ten Year Experience of Radioiodine Dosimetry: is it Useful in the Management of Metastatic Differentiated Thyroid Cancer?
When a fixed activity of radioiodine is given for differentiated thyroid cancer (DTC), absorbed doses of radioiodine can vary widely and are not usually measured. Leeds Cancer Centre has routinely used a form of lesion-specific dosimetry for radioiodine patients. This study investigated if the results of dosimetry influenced treatment decisions for patients with advanced DTC. Since 2005, patients with regionally advanced/metastatic DTC, who underwent radioiodine treatment together with dosimetry, were included in this study. Patients were excluded if their radioiodine post-treatment scan showed no abnormal uptake. Dosimetry was calculated using images taken 2, 3 and 7 days post-radioiodine. Regions of interest were drawn around lesions that required dosimetry and a time-dose activity curve was created. The total cumulative activity was equal to the area under the curve. Each patient's results were prospectively assessed by their oncologist regarding the usefulness of dosimetry in making management decisions. Thirty patients were studied and underwent 102 admissions of radioiodine between them. Dosimetry was carried out during 83 of 102 admissions. An absorbed dose of >20 Gy was taken as significant from dosimetry calculations, following which further radioiodine was considered. In 80% of patients, dosimetry was found to be useful when making treatment decisions. Only on 1/19 admissions did dosimetry calculate a minimum dose above 20 Gy in patients who had a total of four or more admissions for radioiodine. Ten per cent (3/30) had a complete response to radioiodine, both biochemically and radiologically, with a median follow-up of 6.7 months. Thirty-three per cent had a partial response/stable disease to radioiodine. The remainder had progressive disease. The decision to discontinue radioiodine therapy was often based on dosimetry and thyroglobulin results. Dosimetry was very useful for patients with thyroglobulin antibodies. Only 10% had a complete response. Therefore, a significant number of patients became refractory to radioiodine during a course of repeat admissions for treatment. Dosimetry (often together with thyroglobulin and anatomical scans) helped to identify these patients to avoid further futile radioiodine therapy.


Tocilizumab for rheumatoid arthritis.
Tocilizumab, a new biologic that inhibits interleukin-6, is approved for treatment of rheumatoid arthritis (RA) in Europe, Japan and the US. To assess the efficacy and safety of tocilizumab in patients with RA using the data from published randomized or quasi-randomized controlled trials (RCTs). We performed a search of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) up to issue 3, 2009; OVID MEDLINE(1966 to 1 October 2009); CINAHL(1982 to 2009); EMBASE (1980 to week 39, 2009); Science Citation Index (Web of Science) (1945 to 2009) and Current Controlled Trials. Tocilizumab alone or in combination with disease-modifying anti-rheumatic drugs (DMARDs) or biologics compared to placebo or other DMARDs or biologics. Two review authors independently extracted all data including major (ACR50, adverse events, serious adverse events, withdrawals, specific adverse events) and secondary outcomes. We calculated the risk ratio for dichotomous outcomes and mean difference for continuous outcomes. Eight RCTs were included in this systematic review with 3334 participants; 2233 treated with tocilizumab and 1101 controls. Of the 2233, 1561 were treated with tocilizumab 8 mg/kg every four weeks, which is the approved dose. In patients taking concomitant methotrexate, compared to placebo, tocilizumab-treated patients were four times more likely to achieve ACR50 (absolute %, 38.8% versus 9.6%), 11 times more likely to achieve Disease Activity Score (DAS) remission (absolute %, 30.5% versus 2.7%), 1.8 times more likely to achieve clinically meaningful decrease in Health Assessment Questionnaire (HAQ/mHAQ) scores (absolute %, 60.5% versus 34%), 1.2 times more likely to have any adverse event (absolute %, 74% versus 65%) and 0.6 times less likely to withdraw from therapy for any reason (absolute %, 8.1% versus 14.9%). With the limitation that none of the studies were powered for safety as primary outcome, there were no statistically significant differences in serious adverse effects, or withdrawals due to adverse events. A significant increase in total, HDL and LDL cholesterol and triglyceride level was seen in the tocilizumab treated patients. Tocilizumab is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with significant increase in cholesterol levels and in total adverse events. Larger safety studies are needed to address these safety concerns.


[Fibrosarcoma after silicone breast augmentation: is there a connection?].
We describe a 42-year-old woman in whom bilateral fibrosarcoma of the breast was diagnosed 15 years after bilateral breast augmentation with silicone implants. 3 years prior to admission the implants were replaced and 2 years prior to admission mammography showed a nodule in the left breast which biopsy showed to be fibrosarcoma. The implants were removed from both breasts and she was given chemotherapy but later that year underwent bilateral mastectomy. Despite chemotherapy, as well as adjuvant radiotherapy, the disease progressed, with involvement of the lungs and the skin of the left hemithorax. She was admitted repeatedly for severe anemia caused by bleeding from the malignant skin lesions, and died less than 2 years after diagnosis of the disease. Not all reports in the literature find a significant connection between silicone implants and subsequent development of breast cancer, but there are reports that do connect them. Breast fibrosarcoma is not significantly more frequent after silicone augmentation, but still there is controversy as to whether there is a connection between silicone implants and breast malignancy. In the patient we present, the prolonged exposure to silicone may have been a predisposing factor for the development of bilateral fibrosarcoma, since other known risk factors for breast cancer were denied.


Mutation profile of non-small cell lung cancer revealed by next generation sequencing.
Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have rarely been performed in these populations. We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients. Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions. We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.


Site-specific DNA-doxorubicin conjugates display enhanced cytotoxicity to breast cancer cells.
Doxorubicin (Dox) is widely used for breast cancer treatment but causes serious side effects including cardiotoxicity that may adversely impact patient lifespan even if treatment is successful. Herein, we describe selective conjugation of Dox to a single site in a DNA hairpin resulting in a highly stable complex that enables Dox to be used more effectively. Selective conjugation of Dox to G15 in the hairpin loop was verified using site-specific labeling with [2-(15)N]-2'-deoxyguanosine in conjunction with [(1)H-(15)N] 2D NMR, while 1:1 stoichiometry for the conjugate was validated by ESI-QTOF mass spectrometry and UV spectroscopy. Molecular modeling indicated covalently bound Dox also intercalated into the stem of the hairpin and stability studies demonstrated the resulting Dox-conjugated hairpin (DCH) complex had a half-life >30 h, considerably longer than alternative covalent and noncovalent complexes. Secondary conjugation of DCH with folic acid (FA) resulted in increased internalization into breast cancer cells. The dual conjugate, DCH-FA, can be used for safer and more effective chemotherapy with Dox and this conjugation strategy can be expanded to include additional anticancer drugs.


Micrograft and minigraft megasession hair transplantation results after a single session.
The purpose of this article is to share observations made after performing 90 consecutive micrograft and minigraft megasessions for the treatment of male pattern baldness. Micrograft means grafts with 1 or 2 hairs, minigrafts are those with 3 or 4 hairs, and a megasession is a procedure in which more than 1000 micrografts and minigrafts are inserted in a single session. Between March of 1994 and June of 1996, the author performed 90 consecutive micrograft and minigraft megasessions on 86 men and 4 women ranging from 21 to 67 years of age (average age, 42 years). The surgical team consisted of three surgical assistants and a plastic surgeon. Today, usually between 1500 and 2000 grafts per session are performed in about 4 to 6 hours, with up to 2495 grafts done in a single session. All procedures were done under intravenous sedation and local anesthesia. A donor horizontal ellipse of scalp is harvested from the occipital area; the grafts are made out of it and then inserted through small slits. The procedure has been found to be safe and predictable with natural and aesthetically pleasing results, and there were no serious complications. The only complication found in this group was self-resolving inclusion cysts (ingrown hairs) occurring in 9 of 90 patients (10 percent). Even though the hair density achieved in a single megasession is limited, there is a high level of patient satisfaction: 83 of 85 patients were satisfied (97.65 percent).


Sharpened VO2 Phase Transition via Controlled Release of Epitaxial Strain.
Phase transitions in correlated materials can be manipulated at the nanoscale to yield emergent functional properties, promising new paradigms for nanoelectronics and nanophotonics. Vanadium dioxide (VO2), an archetypal correlated material, exhibits a metal-insulator transition (MIT) above room temperature. At the thicknesses required for heterostructure applications, such as an optical modulator discussed here, the strain state of VO2 largely determines the MIT dynamics critical to the device performance. We develop an approach to control the MIT dynamics in epitaxial VO2 films by employing an intermediate template layer with large lattice mismatch to relieve the interfacial lattice constraints, contrary to conventional thin film epitaxy that favors lattice match between the substrate and the growing film. A combination of phase-field simulation, in situ real-time nanoscale imaging, and electrical measurements reveals robust undisturbed MIT dynamics even at preexisting structural domain boundaries and significantly sharpened MIT in the templated VO2 films. Utilizing the sharp MIT, we demonstrate a fast, electrically switchable optical waveguide. This study offers unconventional design principles for heteroepitaxial correlated materials, as well as novel insight into their nanoscale phase transitions.


An inventory of biodiversity data sources for conservation monitoring.
Many conservation managers, policy makers, businesses and local communities cannot access the biodiversity data they need for informed decision-making on natural resource management. A handful of databases are used to monitor indicators against global biodiversity goals but there is no openly available consolidated list of global data sets to help managers, especially those in high-biodiversity countries. We therefore conducted an inventory of global databases of potential use in monitoring biodiversity states, pressures and conservation responses at multiple levels. We uncovered 145 global data sources, as well as a selection of global data reports, links to which we will make available on an open-access website. We describe trends in data availability and actions needed to improve data sharing. If the conservation and science community made a greater effort to publicise data sources, and make the data openly and freely available for the people who most need it, we might be able to mainstream biodiversity data into decision-making and help stop biodiversity loss.


Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol.
While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.


Albumin decrease is associated with spontaneous preterm delivery within 48 h in women with threatened preterm labor.
Threatened preterm labor (TPTL) accounts for ∼30% of pregnancy-related hospital admissions. Maternal peripheral leukocytes can be used to monitor a variety of physiological processes occurring in the body. Two high-throughput mass spectrometry methodologies, SWATH and iTRAQ, were used to study differentially expressed peripheral blood leukocyte lysate proteins in symptomatic women admitted for TPTL who had a preterm birth within 48 h (n = 16) and those who did not (n = 24). The SWATH spectral library consisted of 783 proteins. SWATH methodology quantified 258 proteins (using ≥2 peptides) and 5 proteins (ALBU, ANXA6, HNRPK, HSP90A, and PDIA1) were differentially expressed (p < 0.05, Mann-Whitney U). iTRAQ workflow identified 765 proteins; 354 proteins were quantified and 14 proteins (MIF, UBIQ, HXK3, ALBU, HNRPD, ST1A2, RS15A, RAP1B, CAN1, IQGA2, ST1A1, COX5A, ADDA, and UBQL1) were significantly different between the two groups of women (p < 0.05, Mann-Whitney U). Albumin was the only common differentially expressed protein in both SWATH (28% decrease) and iTRAQ studies (45% decrease). This decrease in albumin was validated using ELISA (11% decrease, p < 0.05, Mann-Whitney U) in another 23 TPTL women. This work suggests that albumin is a broad indicator of leukocyte activation with impending preterm birth and provides new future work directions to understand the pathophysiology of TPTL.


Efficient Permeance Recovery of Organically Fouled Graphene Oxide Membranes.
The emergence of facile approaches for the large-scale production of graphene oxide (GO) membranes necessitates a clearer understanding of their potential to foul and, more importantly, strategies for efficient recovery of membrane performance following fouling. Here, we systematically investigated the feasibility of water, ethanol, and hypochlorite as cleaning agents to remove organic foulants over a GO membrane. Among them, 100 ppm hypochlorite solution showed a remarkable ability to remove bovine serum albumin (BSA) and could recover the membrane flux up to 98% after five cycles of BSA filtration and cleaning. The potential of hypochlorite was also demonstrated for permeance recovery during molecular filtration of tannic acid and methyl blue. Scanning electron microscopy, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and X-ray diffraction (XRD) analyses were used to study the oxidative effects of hypochlorite on the GO membrane, and it was determined that exposure to higher concentrations of hypochlorite (>1000 ppm) degrades the structure of GO membrane and deteriorates the membrane performance after three cycles of cleaning. The studies demonstrate that the use of a modest concentration of hypochlorite is effective in restoring permeance of this class of high flux nanofiltration membranes.


The role of pre-treatment white matter abnormalities in developing white matter changes following whole brain radiation: a volumetric study.
White matter injury is a known complication of whole brain radiation (WBRT). Little is known about the factors that predispose a patient to such injury. The current study used MR volumetrics to examine risk factors, in particular the influence of pre-treatment white matter health, in developing white matter change (WMC) following WBRT. Thirty-four patients with unilateral metastatic disease underwent FLAIR MRI pre-treatment and at several time points following treatment. The volume of abnormal FLAIR signal in the white matter was measured in the hemisphere contralateral to the diseased hemisphere at each time point. Analyses were restricted to the uninvolved hemisphere to allow for the measurement of WBRT effects without the potential confounding effects of the disease on imaging findings. The relationship between select pre-treatment clinical variables and the degree of WMC following treatment was examined using correlational and regression based analyses. Age when treated and volume of abnormal FLAIR prior to treatment were significantly associated with WMC following WBRT; however, pre-treatment FLAIR volume was the strongest predictor of post-treatment WMCs. Age did not add any predictive value once white matter status was considered. No significant relationships were found between biological equivalent dose and select cerebrovascular risk factors (total glucose, blood pressure, BMI) and development of WMCs. The findings from this study identify pre-treatment white matter health as an important risk factor in developing WMC following WBRT. This information can be used to make more informed decisions and counsel patients on their risk for treatment effects.


[Walking in the International Four Days Marches Nijmegen: an estimation of the risks].
In 2006, the annual Four Days Marches in Nijmegen, the Netherlands, were cancelled after the first day because two participants had died, and many had become unwell while walking in unusually high ambient temperatures. During the 2007 edition, an observational study of the physiological impact and health risks for walkers was carried out. This time, the ambient conditions were mild. Most participants (90.7%) finished the march without serious complaints or clinical complications, despite significant disturbances in fluid balance and electrolytes. The training level of the participants varied considerably. If we compare the results of this physiological study with studies during marathons, similarities in physiological adaptions are found, most probably due to the same biological mechanisms. However, the participants of the Four Days Marches are incomparable with long-distance runners. There is as yet no well-founded advice concerning the fluid intake of Four Days Marches participants. Increase or decrease in body weight may be an interesting diagnostic tool to measure the risk of dehydration or overhydration.


Forming impressions of facial attractiveness is mandatory.
First impressions of social traits, such as attractiveness, from faces are often claimed to be made automatically, given their speed and reliability. However, speed of processing is only one aspect of automaticity. Here we address a further aspect, asking whether impression formation is mandatory. Mandatory formation requires that impressions are formed about social traits even when this is task-irrelevant, and that once formed, these impressions are difficult to inhibit. In two experiments, participants learned what new people looked like for the purpose of future identification, from sets of images high or low in attractiveness. They then rated middle-attractiveness images of each person, for attractiveness. Even though instructed to rate the specific images, not the people, their ratings were biased by the attractiveness of the learned images. A third control experiment, with participants rating names, demonstrated that participants in Experiments 1 and 2 were not simply rating the people, rather than the specific images as instructed. These results show that the formation of attractiveness impressions from faces is mandatory, thus broadening the evidence for automaticity of facial impressions. The mandatory formation of impressions is likely to have an important impact in real-world situations such as online dating sites.


Rise of the Machines: The Inevitable Evolution of Medicine and Medical Laboratories Intertwining with Artificial Intelligence-A Narrative Review.
Laboratory medicine has evolved from a mainly manual profession, providing few selected test results to a highly automated and standardized medical discipline, generating millions of test results per year. As the next inevitable evolutional step, artificial intelligence (AI) algorithms will need to assist us in structuring and making sense of the masses of diagnostic data collected today. Such systems will be able to connect clinical and diagnostic data and to provide valuable suggestions in diagnosis, prognosis or therapeutic options. They will merge the often so separated worlds of the laboratory and the clinics. When used correctly, it will be a tool, capable of freeing the physicians time so that he/she can refocus on the patient. In this narrative review I therefore aim to provide an overview of what AI is, what applications currently are available in healthcare and in laboratory medicine in particular. I will discuss the challenges and pitfalls of applying AI algorithms and I will elaborate on the question if healthcare workers will be replaced by such systems in the near future.


Pharmacokinetics of cefatrizine after oral administration in human volunteers.
The oral bioavailability of cefatrizine was studied in four groups, each of ten healthy young male volunteers. Capsules and suspension formulations were each administered at doses of 250 and 500 mg. Both the capsules and suspensions had mean peak plasma levels at 1.6 h at both dose levels. Mean peak plasma levels were 4.1 and 4.3 micrograms/ml for the 250 mg capsule and suspension doses respectively and 7.1 and 7.5 micrograms/ml for the 500 mg capsules and suspension doses respectively. The overall mean half-life was 1.7 h. For both types of formulations and at both dose levels 63-65% of the doses were excreted in the urine as intact cefatrizine, 85% of this amount within 8 h. The overall mean renal clearance was 157 ml/min. The cefatrizine capsule and suspension formulations were completely bioequivalent in regard to both rate and extent of bioavailability. Plasma concentrations and urinary recoveries of cefatrizine were higher than those previously reported, due to precautions taken in sample collection and storage.


Carried Weight Affects Walking Speed Monitoring with the IngVaL System.
Earlier work has shown that the IngVaL pedobarography system can estimate walking speed during indoor walking using only three forefoot sensors. The aim of this study was to examine if monitoring of walking speed using data from these three forefoot sensors is affected of the weight a person carries, if the person performs a walk in a set speed on the treadmill. Shoe insoles with force sensing resistors were connected to an electronic unit for signal conditioning and sampling and then the data was sent via Bluetooth to a tablet. Fifteen test persons walked five times each carrying five different weights on the treadmill at 1 m/s. The force-time integrals for the sum of the three forefoot sensors were calculated. This study shows that the force-time integrals for the three forefoot sensors shows a linear relationship with the carried weight as long as the person is not fatigued.


Succinylcholine versus rocuronium for rapid sequence intubation in intensive care: a prospective, randomized controlled trial.
Succinylcholine and rocuronium are widely used to facilitate rapid sequence induction (RSI) intubation in intensive care. Concerns relate to the side effects of succinylcholine and to slower onset and inferior intubation conditions associated with rocuronium. So far, succinylcholine and rocuronium have not been compared in an adequately powered randomized trial in intensive care. Accordingly, the aim of the present study was to compare the incidence of hypoxemia after rocuronium or succinylcholine in critically ill patients requiring an emergent RSI. This was a prospective randomized controlled single-blind trial conducted from 2006 to 2010 at the University Hospital of Basel. Participants were 401 critically ill patients requiring emergent RSI. Patients were randomized to receive 1 mg/kg succinylcholine or 0.6 mg/kg rocuronium for neuromuscular blockade. The primary outcome was the incidence of oxygen desaturations defined as a decrease in oxygen saturation ≥ 5%, assessed by continuous pulse oxymetry, at any time between the start of the induction sequence and two minutes after the completion of the intubation. A severe oxygen desaturation was defined as a decrease in oxygen saturation ≥ 5% leading to a saturation value of ≤ 80%. There was no difference between succinylcholine and rocuronium regarding oxygen desaturations (succinylcholine 73/196; rocuronium 66/195; P = 0.67); severe oxygen desaturations (succinylcholine 20/196; rocuronium 20/195; P = 1.0); and extent of oxygen desaturations (succinylcholine -14 ± 12%; rocuronium -16 ± 13%; P = 0.77). The duration of the intubation sequence was shorter after succinycholine than after rocuronium (81 ± 38 sec versus 95 ± 48 sec; P = 0.002). Intubation conditions (succinylcholine 8.3 ± 0.8; rocuronium 8.2 ± 0.9; P = 0.7) and failed first intubation attempts (succinylcholine 32/200; rocuronium 36/201; P = 1.0) did not differ between the groups. In critically ill patients undergoing emergent RSI, incidence and severity of oxygen desaturations, the quality of intubation conditions, and incidence of failed intubation attempts did not differ between succinylcholine and rocuronium. ClinicalTrials.gov, number NCT00355368.


Exploring why girls smoke in Malaysia--a qualitative approach.
The fast increase in the rate of uptake of smoking amongst adolescent girls in Malaysia is a public health concern. The objective of this study was to investigate factors that influenced the initiation of smoking and the effects of advertisement on consolidating the smoking habit among teenage girls in the urban city of Kuala Lumpur. Qualitative research was conducted using both interviews and focus group discussions with groups of adolescent girls. Data collected was analysed using grounded thematic theory methodology and validated using methodological triangulation. The reasons for initiating smoking elicited from the study can be grouped into 4 general themes; influence by peers, influence of seeing parents smoking, misguided belief that it could alleviate stress and finally that it would impress others. Smoking imageries in media and advertisements were not primary influencing factors in the initiation of smoking but it encouraged them to progress to become regulars. Ways should be sought to empower girls to feel more confident about resisting pressures to initiate smoking. This could be done through activities such as positive peer sports, education on how to alleviate stress and curbing of smoking imageries in the media.


Accelerated telomere shortening in fibroblasts after extended periods of confluency.
Telomere length in MRC-5 fibroblasts remains constant if the cells are proliferation-inhibited for up to 3 months by confluency. However, the apparent frequency of single-stranded sites in telomeres, measured as sensitivity to degradation by S1 nuclease, increases about fourfold during this extended inhibition of proliferation. After release of the cells, the frequency of telomeric single-stranded sites decreases to control values, and the telomere shortening rate increases about threefold as compared to controls proliferating without inhibition. This acceleration is transitory, the telomere shortening rate decreases to control values after about two population doublings after release. Finally, temporarily arrested fibroblast populations senesce at a lower cumulative population doubling level, but at about the same telomere length, as continuously proliferating controls. The data suggest that metabolic time-dependent single-strand degradation is a major cause of telomere shortening. They support the idea that telomere shortening plays an important role in triggering cellular senescence.


Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos.
Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiation with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults.


Author´s answer to: "Effect of adacolumn® in ulcerative colitis with COVID-19".
We have read with interest the article published by Pérez et al., we really appreciate their interesting comments and would like to qualify some points. With the except of the clinical practice, currently there is no recommendation based on scientific evidence about the use of apheresis in the treatment of ulcerative colitis (UC), and even less in Crohn's disease (CD). However, the results obtained in the case of Pérez et al. in relation to systemic inflammation and pulmonary clinical improvement are very interesting from a pathophysiological and clinical point of view.


Cognitive maps as orienting schemata.
A "point-to-unseen-targets" task was used to test two theories about the nature of cognitive mapping. The hypothesis that a cognitive map is like a "picture in the head" predicts that (a) the cognitive map should have a preferred orientation and (b) all coded locations should be equally available. These predictions were confirmed in Experiments 1 and 3 when targets were cities in the northeastern United States and learning was from a map. The theory that a cognitive map is an orienting schema predicts that the cognitive map should have no preferred orientation and that targets in front of the body should be localized faster than targets behind the body. These predictions were confirmed in Experiments 1 and 2 when targets were local landmarks that had been learned via direct experience. In Experiment 3, when cities in the Northeast were targets and geographical knowledge had been acquired, in part, by traveling in the Northeast, the observed latency profiles were not as predicted by either theory of cognitive mapping. The results suggest that orienting schemata direct orientation with respect to local environments, but that orientation with respect to large geographical regions is supported by a different type of cognitive structure.


Intra- and interobserver error of the Greulich-Pyle method as used on a Danish forensic sample.
The Section of Forensic Medicine at the University of Copenhagen performs age evaluations of the living at the request of the police. The established procedure in these cases involves: (1) a physical examination; (2) an odontological examination based on evaluation of an orthopantomogram and intraoral dental radiographs. Different methods are used depending on the maturity of the individual examined; and (3) a carpal X-ray examination, using the Greulich and Pyle Atlas (GPA) method. We present the results of intra- and interobserver tests of carpal X-rays in blind trials, and a comparison of the age estimations by carpal X-rays and odontological age estimation. We retrieved 159 cases from the years 2000-2002 (inclusive). The intra- and interobserver errors are overall small. We found full agreement in 126/159 cases, and this was between experienced users and novices. Overall, the mean difference was 0.053 years, with a standard deviation of +/-0.567 years. Our results show that the direct and naïve use of the GPA is simple and reproducible, even when applied by non-experienced users. This is probably also why the method is still widely applied, even though other authors have stated that atlas-based techniques are obsolete and ought to be replaced by other methods. Specifically, the GPA test sample consisted of American "white" children "above average in economic and educational status", leading to the question as to how comparable subjects being scored by the GPA method today are to this original sample. Indeed, we found a minor difference in the age estimations for older juveniles between odontologists and radiologists, which may indicate that more studies on comparative dental and skeletal aging for geographically different populations would be beneficial. Finally, if using the GPA method in legal cases, we would advise that one should closely adhere to the standard deviations given, and intermediary scores should be noted and not just a resultant age. The final age statement should also address the problems of reference populations.


Design and Synthesis of Ketenimine Sulfonamide Conjugates through Multicomponent Reactions; A Combined Cytotoxic Analysis and Computational Exploration.
Multicomponent reactions involving zwitterion generated from dimethyl acetylenedicarboxylate, aryl sulfonamide, and isocyanide to generate sulfonamide-conjugated ketenimines is reported. The synthetic strategy adopted is highly atom economical and stereoselective. Ketenimine sulfonamide analogues are key intermediates for further synthetic conversions to generate a combinatorial library of compounds. Furthermore, sulfonamide compounds are known to possess a broad spectrum of biological applications. All the novel molecules synthesized exhibit the potential to target the nonhomologous DNA end-joining (NHEJ) pathway with cytotoxic ability. Computational studies compliment the in vitro biological assays of the 8 small-molecule inhibitors. DNA double-strand breaks (DSBs) are considered as the most lethal among different DNA damages. NHEJ repairs about 70% of the DSBs generated in cells within mammals. The DNA-dependent protein kinase catalytic subunit is one of the PI3 kinases associated with NHEJ. Compounds DK01-DK08 were investigated for their ability to induce cancer cell death by treating with two leukemic cell lines where NHEJ is high. Results showed that bromoaryl (DK04)- and nitroaryl (DK05)-conjugated molecules showed excellent biological activity, having IC50 values of ∼2 μM in Nalm6 cell lines.


The impact of the rising colorectal cancer incidence in young adults on the optimal age to start screening: Microsimulation analysis I to inform the American Cancer Society colorectal cancer screening guideline.
In 2016, the Microsimulation Screening Analysis-Colon (MISCAN-Colon) model was used to inform the US Preventive Services Task Force colorectal cancer (CRC) screening guidelines. In this study, 1 of 2 microsimulation analyses to inform the update of the American Cancer Society CRC screening guideline, the authors re-evaluated the optimal screening strategies in light of the increase in CRC diagnosed in young adults. The authors adjusted the MISCAN-Colon model to reflect the higher CRC incidence in young adults, who were assumed to carry forward escalated disease risk as they age. Life-years gained (LYG; benefit), the number of colonoscopies (COL; burden) and the ratios of incremental burden to benefit (efficiency ratio [ER] = ΔCOL/ΔLYG) were projected for different screening strategies. Strategies differed with respect to test modality, ages to start (40 years, 45 years, and 50 years) and ages to stop (75 years, 80 years, and 85 years) screening, and screening intervals (depending on screening modality). The authors then determined the model-recommended strategies in a similar way as was done for the US Preventive Services Task Force, using ER thresholds in accordance with the previously accepted ER of 39. Because of the higher CRC incidence, model-predicted LYG from screening increased compared with the previous analyses. Consequently, the balance of burden to benefit of screening improved and now 10-yearly colonoscopy screening starting at age 45 years resulted in an ER of 32. Other recommended strategies included fecal immunochemical testing annually, flexible sigmoidoscopy screening every 5 years, and computed tomographic colonography every 5 years. This decision-analysis suggests that in light of the increase in CRC incidence among young adults, screening may be offered earlier than has previously been recommended. Cancer 2018;124:2964-73. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.


An approach to rapid calculation of temperature change in tissue using spatial filters to approximate effects of thermal conduction.
We present an approach to performing rapid calculations of temperature within tissue by interleaving, at regular time intervals, 1) an analytical solution to the Pennes (or other desired) bioheat equation excluding the term for thermal conduction and 2) application of a spatial filter to approximate the effects of thermal conduction. Here, the basic approach is presented with attention to filter design. The method is applied to a few different cases relevant to magnetic resonance imaging, and results are compared to those from a full finite-difference (FD) implementation of the Pennes bioheat equation. It is seen that results of the proposed method are in reasonable agreement with those of the FD approach, with about 15% difference in the calculated maximum temperature increase, but are calculated in a fraction of the time, requiring less than 2% of the calculation time for the FD approach in the cases evaluated.


Contact-dependent T cell activation and T cell stopping require talin1.
T cell-APC contact initiates T cell activation and is maintained by the integrin LFA-1. Talin1, an LFA-1 regulator, localizes to the immune synapse (IS) with unknown roles in T cell activation. In this study, we show that talin1-deficient T cells have defects in contact-dependent T cell stopping and proliferation. Although talin1-deficient T cells did not form stable interactions with APCs, transient contacts were sufficient to induce signaling. In contrast to prior models, LFA-1 polarized to T cell-APC contacts in talin1-deficient T cells, but vinculin and F-actin polarization at the IS was impaired. These results indicate that T cell proliferation requires sustained, talin1-mediated T cell-APC interactions and that talin1 is necessary for F-actin polarization and the stability of the IS.


Structural constraints of functional connectivity drive cognitive impairment in the early stages of multiple sclerosis.
The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural-functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure-function relationships. Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural-functional coupling had increased significantly after 5 years. This structural-functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability.


Alu- and 7SL RNA Analogues Suppress MCF-7 Cell Viability through Modulating the Transcription of Endoplasmic Reticulum Stress Response Genes.
11% of the human genome is composed of Alu-retrotransposons, whose transcription by RNA polymerase III (Pol III) leads to the accumulation of several hundreds to thousands of Alu-RNA copies in the cytoplasm. Expression of Alu-RNA Pol III is significantly increased at various levels of stress, and the increase in the Alu-RNA level is accompanied by a suppression of proliferation, a decrease in viability, and induction of apoptotic processes in human cells. However, the question about the biological functions of Pol III Alu-transcripts, as well as their mechanism of action, remains open. In this work, analogues of Alu-RNA and its evolutionary ancestor, 7SL RNA, were synthesized. Transfection of human breast adenocarcinoma MCF-7 cells with the Alu-RNA and 7SL RNA analogues is accompanied by a decrease in viability and by induction of proapoptotic changes in these cells. The analysis of the combined action of these analogues and actinomycin D or tamoxifen revealed that the decreased viability of MCF-7 cells transfected with Alu-RNA and 7SL RNA was due to the modulation of transcription. A whole transcriptome analysis of gene expression revealed that increased gene expression of the transcription regulator NUPR1 (p8), as well as the transcription factor DDIT3 (CHOP), occurs under the action of both the Alu- and 7SL RNA analogues on MCF-7 cells. It has been concluded that induction of proapoptotic changes in human cells under the influence of the Alu-RNA and 7SL RNA analogues is related to the transcriptional activation of the genes of cellular stress factors, including the endoplasmic reticulum stress response factors.


Immune regulation by CD4+CD25+ T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls.
CD4+CD25+ regulatory T (Treg) cells and the cytokines IL-10 or TGF-beta play key roles in the maintenance of T cell homeostasis and tolerance to infectious and non-infectious antigens such as allergens. To investigate the regulation of immune responses to birch pollen allergen compared with influenza antigen by Treg cells obtained from birch pollen-allergic patients and non-allergic controls. Peripheral blood was collected from 10 birch pollen-allergic patients and 10 non-allergic healthy controls. CD4+CD25+ and CD4+CD25- cells isolated by magnetic-activated cell sorting were co-cultured and stimulated with birch pollen extract or influenza vaccine in the absence or presence of anti-IL-10 or soluble TGF-betaRII. CD4+CD25+ cells from non-allergic controls were able to suppress influenza antigen and birch pollen stimulated effector cell proliferation, whereas CD4+CD25+ cells from allergic patients suppressed influenza antigen-, but not birch pollen-stimulated proliferation. The production of Th1 cytokines, but not Th2 cytokines, was suppressed by CD4+CD25+ cells from both allergic patients and controls, upon stimulation with birch pollen extract. Neutralization of IL-10 led to significantly increased production of IFN-gamma in cultures with CD4+CD25- T effector cells. In addition, six-fold higher concentrations of TNF-alpha were detected after neutralization of IL-10 in both CD4+CD25- and CD4+CD25+ cell cultures from allergic patients and controls. We demonstrate that the allergen-specific suppressive function of CD4+CD25+ cells from allergic patients is impaired compared with non-allergic controls. Moreover, neutralization of IL-10 enhances the production of TNF-alpha, suggesting counter-acting properties of IL-10 and TNF-alpha, where IL-10 promotes tolerance and suppression by Treg cells and TNF-alpha promotes inflammatory responses.


Evidence for Cerebellar Contributions to Adaptive Plasticity in Speech Perception.
Human speech perception rapidly adapts to maintain comprehension under adverse listening conditions. For example, with exposure listeners can adapt to heavily accented speech produced by a non-native speaker. Outside the domain of speech perception, adaptive changes in sensory and motor processing have been attributed to cerebellar functions. The present functional magnetic resonance imaging study investigates whether adaptation in speech perception also involves the cerebellum. Acoustic stimuli were distorted using a vocoding plus spectral-shift manipulation and presented in a word recognition task. Regions in the cerebellum that showed differences before versus after adaptation were identified, and the relationship between activity during adaptation and subsequent behavioral improvements was examined. These analyses implicated the right Crus I region of the cerebellum in adaptive changes in speech perception. A functional correlation analysis with the right Crus I as a seed region probed for cerebral cortical regions with covarying hemodynamic responses during the adaptation period. The results provided evidence of a functional network between the cerebellum and language-related regions in the temporal and parietal lobes of the cerebral cortex. Consistent with known cerebellar contributions to sensorimotor adaptation, cerebro-cerebellar interactions may support supervised learning mechanisms that rely on sensory prediction error signals in speech perception.


On the discrepant results in synchrony judgment and temporal-order judgment tasks: a quantitative model.
Research on the perception of temporal order uses either temporal-order judgment (TOJ) tasks or synchrony judgment (SJ) tasks, in both of which two stimuli are presented with some temporal delay and observers must judge the order of presentation. Results generally differ across tasks, raising concerns about whether they measure the same processes. We present a model including sensory and decisional parameters that places these tasks in a common framework that allows studying their implications on observed performance. TOJ tasks imply specific decisional components that explain the discrepancy of results obtained with TOJ and SJ tasks. The model is also tested against published data on audiovisual temporal-order judgments, and the fit is satisfactory, although model parameters are more accurately estimated with SJ tasks. Measures of latent point of subjective simultaneity and latent sensitivity are defined that are invariant across tasks by isolating the sensory parameters governing observed performance, whereas decisional parameters vary across tasks and account for observed differences across them. Our analyses concur with other evidence advising against the use of TOJ tasks in research on perception of temporal order.


Patient values and preferences regarding VTE disease: a systematic review to inform American Society of Hematology guidelines.
Values and preferences relate to the importance that patients place on health outcomes (eg, bleeding, having a deep venous thrombosis) and are essential when weighing benefits and harms in guideline recommendations. To inform the American Society of Hematology guidelines for management of venous thromboembolism (VTE) disease, we conducted a systematic review of patients' values and preferences related to VTE. We searched Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature from inception to April of 2018 (PROSPERO-CRD42018094003). We included quantitative and qualitative studies. We followed Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance for rating the certainty and presenting findings for quantitative research about the relative importance of health outcomes and a grounded theory approach for qualitative thematic synthesis. We identified 14 quantitative studies (2465 participants) describing the relative importance of VTE-related health states in a widely diverse population of patients, showing overall small to important impact on patients' lives (certainty of the evidence from low to moderate). Additionally, evidence from 34 quantitative studies (6424 participants) and 15 qualitative studies (570 participants) revealed that patients put higher value on VTE risk reduction than on the potential harms of the treatment (certainty of evidence from low to moderate). Studies also suggested a clear preference for oral medication over subcutaneous medication (moderate certainty). The observed variability in health state values may be a result of differences in the approaches used to elicit them and the diversity of included populations rather than true variability in values. This finding highlights the necessity to explore the variability induced by different approaches to ascertain values.


In search of an ideal test for diagnosis and prognosis of kala-azar.
The latex agglutination test (KAtex), direct agglutination test (DAT), and the rK39 immuno-chromatographic strip test (dipstick test) were evaluated for their role in the diagnosis and prognosis of visceral leishmaniasis (kala-azar) in India. Sera and urine samples from 455 subjects--150 confirmed visceral leishmaniasis cases, 160 endemic controls, 100 non-endemic controls, and 45 other febrile diseases--were included in the study. The sensitivity of the KAtex, DAT, and rK39 strip test was 87% [95% confidence interval (CI) 80-96], 93.3% (95% CI 88-100), and 98% (95% CI 93-100) respectively. The specificity of these tests was 98% (95% CI 93-100), 93% (95% CI 87-100), and 89% (95% CI 82-97) for the KAtex, DAT, and rK39 strip test respectively. Fifty cases were followed up and subjected to the KAtex, DAT, and rK39 strip test after 30 days of successful treatment. The DAT and rK39 strip test showed positive results in all the 50 cases whereas the KAtex showed no positive reaction in any case. Based on the results, it is concluded that the sensitivity and specificity of the DAT and rK39 strip test are comparable but the greater convenience of use of the strip test makes it a better tool for the diagnosis of visceral leishmaniasis in the peripheral areas of endemic regions whereas the sensitivity of the KAtex needs to be improved to promote its use as a first-line diagnostic test in the field-setting. It may be used for the prognosis of the disease as antigen becomes undetectable in urine after 30 days of the completion of the treatment. Alternatively, it can be used as an adjunct with rK39 for sero-epidemiological surveys.