Association between colorectal cancer and Streptococcus gallolyticus subsp. pasteuranus (former S. bovis) endocarditis: clinical relevance and cues for microbiota science. Case report and review of the literature.
The purpose of this paper is to contextualize the case of a patient with a synchronous diagnosis of colorectal cancer (CRC) and endocarditis from S. gallolyticus subsp. pasteuranus (former S. Bovis) within the current evidence, in order to determine if this condition is indicative of an underlying CRC and if it has any pathophysiologic significance. First, we describe the clinical case. Then, we review the literature focused on the association between infections from the former S. Bovis group and CRC and on the possible role of certain microbiota species on the occurrence of CRC. At last, we discuss the implications of this case considering the current evidence. There is a strong association between all the species of the former S. Bovis group and CRC. There is initial evidence that these bacteria may contribute to CRC by a genomic passenger mechanism. There are two main conclusions for this paper. The first one is that CRC neoplasms and endocarditis from all species of the former S. bovis group have a strong association. Any case of infection by these subspecies should prompt to a diagnostic completion by colonoscopy. The second one is that there is an increased need for detailed reports/series and original articles based on the evaluation of gut microbiota in patients with CRC, with the aim to clarify if the association between bacteria and CRC is causative or sporadic and to better understand the possible causative mechanism of specific bacteria in initiating and promoting CRC.


DNA sequence analysis of serologically detected ELA class II haplotypes at the equine DQ beta locus.
The genetic diversity at the ELA DQ beta locus was investigated using polymerase chain reaction and DNA sequencing. Based upon serological methods 16 class II homozygous animals were selected and their genomic DNA was used. A DQ beta gene from an equine cDNA library was also sequenced. Our methodology and the similarity between the genomic and the cDNA sequences suggest that the studied locus is expressed on equine lymphocytes. In the predicted amino acid sequence the most extensive variation is located at residues 56-60. The pattern of these five amino acids is strongly correlated to the serological ELA class II specificities (W13, W22, W23, Be200). The alleles corresponding to the W23 specificity are the most divergent among the equine DQ beta alleles and also from other mammalian DQ beta sequences.


Magnetoliposomes Based on Shape Anisotropic Calcium/Magnesium Ferrite Nanoparticles as Nanocarriers for Doxorubicin.
Multifunctional lipid nanocarriers are a promising therapeutic approach for controlled drug release in cancer therapy. Combining the widely used liposome structure with magnetic nanoparticles in magnetoliposomes allies, the advantages of using liposomes include the possibility to magnetically guide, selectively accumulate, and magnetically control the release of drugs on target. The effectiveness of these nanosystems is intrinsically related to the individual characteristics of the two main components-lipid formulation and magnetic nanoparticles-and their physicochemical combination. Herein, shape-anisotropic calcium-substituted magnesium ferrite nanoparticles (Ca0.25Mg0.75Fe2O4) were prepared for the first time, improving the magnetic properties of spherical counterparts. The nanoparticles revealed a superparamagnetic behavior, high saturation magnetization (50.07 emu/g at 300 K), and a large heating capacity. Furthermore, a new method for the synthesis of solid magnetoliposomes (SMLs) was developed to enhance their magnetic response. The manufacturing technicalities were optimized with different lipid compositions (DPPC, DPPC/Ch, and DPPC/DSPE-PEG) originating nanosystems with optimal sizes for biomedical applications (around or below 150 nm) and low polydispersity index. The high encapsulation efficiency of doxorubicin in these magnetoliposomes was proven, as well as the ability of the drug-loaded nanosystems to interact with cell membrane models and release DOX by fusion. SMLs revealed to reduce doxorubicin interaction with human serum albumin, contributing to a prolonged bioavailability of the drug upon systemic administration. Finally, the drug release kinetic assays revealed a preferable DOX release at hyperthermia temperatures (42 °C) and acidic conditions (pH = 5.5), indicating them as promising controlled release nanocarriers by either internal (pH) and external (alternate magnetic field) stimuli in cancer therapy.


Autonomic effects induced by pharmacological activation and inhibition of Raphe Pallidus neurons in anaesthetized adult pigs.
The Raphe Pallidus (RPa) is a region of the brainstem that was shown to modulate the sympathetic outflow to many tissues and organs involved in thermoregulation and energy expenditure. In rodents, the pharmacological activation of RPa neurons was shown to increase the activity of the brown adipose tissue, heart rate, and expired CO2 , whereas their inhibition was shown to induce cutaneous vasodilation and a state of hypothermia that, when prolonged, leads to a state resembling torpor referred to as synthetic torpor. If translatable to humans, this synthetic torpor-inducing procedure would be advantageous in many clinical settings. A first step to explore such translatability, has been to verify whether the neurons within the RPa play the same role described for rodents in a larger mammal such as the pig. In the present study, we show that the physiological responses inducible by the pharmacological stimulation of RPa neurons are very similar to those observed in rodents. Injection of the GABAA agonist GABAzine in the RPa induced an increase in heart rate (from 99 to 174 bpm), systolic (from 87 to 170 mm Hg) and diastolic (from 51 to 98 mm Hg) arterial pressure, and end-tidal CO2 (from 49 to 62 mm Hg). All these changes were reversed by the injection in the same area of the GABAA agonist muscimol. These results support the possibility for RPa neurons to be a key target in the research for a safe and effective procedure for the induction of synthetic torpor in humans.


De novo identification of essential protein domains from CRISPR-Cas9 tiling-sgRNA knockout screens.
High-throughput CRISPR-Cas9 knockout screens using a tiling-sgRNA design permit in situ evaluation of protein domain function. Here, to facilitate de novo identification of essential protein domains from such screens, we propose ProTiler, a computational method for the robust mapping of CRISPR knockout hyper-sensitive (CKHS) regions, which refer to the protein regions associated with a strong sgRNA dropout effect in the screens. Applied to a published CRISPR tiling screen dataset, ProTiler identifies 175 CKHS regions in 83 proteins. Of these CKHS regions, more than 80% overlap with annotated Pfam domains, including all of the 15 known drug targets in the dataset. ProTiler also reveals unannotated essential domains, including the N-terminus of the SWI/SNF subunit SMARCB1, which is validated experimentally. Surprisingly, the CKHS regions are negatively correlated with phosphorylation and acetylation sites, suggesting that protein domains and post-translational modification sites have distinct sensitivities to CRISPR-Cas9 mediated amino acids loss.


Financial Justification for Interventional Pulmonology Programs: Terminology and Programmatic Models.
Interventional pulmonology programs provide clinical benefit to patients and are financially sustainable. To appreciate and illustrate the economic value of interventional pulmonology programs to hospital systems, physicians must have an understanding of basic health-care finance. Total revenue, adjusted gross revenue, contribution margin, variable direct costs, and indirect costs are terms that are essential for understanding the finances of bronchoscopy. Command of such vocabulary and its application is crucial for interventional pulmonologists to successfully establish financially sustainable bronchoscopy programs. Two significant features of an economically sustainable bronchoscopy program are high procedural volume and low direct cost per case. Interventional pulmonology programs are valuable to the patients being served and hospitals as a whole. Consideration of the various factors needed to maintain financial sustainability is essential to improve the quality of care for patients because the cost of care remains a critical driver in defining value.


Selection of hyperadherent mutants in Pseudomonas putida biofilms.
A number of genetic determinants required for bacterial colonization of solid surfaces and biofilm formation have been identified in different micro-organisms. There are fewer accounts of mutations that favour the transition to a sessile mode of life. Here we report the isolation of random transposon Pseudomonas putida KT2440 mutants showing increased biofilm formation, and the detailed characterization of one of them. This mutant exhibits a complex phenotype, including altered colony morphology, increased production of extracellular polymeric substances and enhanced swarming motility, along with the formation of denser and more complex biofilms than the parental strain. Sequence analysis revealed that the pleiotropic phenotype exhibited by the mutant resulted from the accumulation of two mutations: a transposon insertion, which disrupted a predicted outer membrane lipoprotein, and a point mutation in lapG, a gene involved in the turnover of the large adhesin LapA. The contribution of each alteration to the phenotype and the possibility that prolonged sessile growth results in the selection of hyperadherent mutants are discussed.


A Well Infant With Coronavirus Disease 2019 With High Viral Load.
A well 6-month-old infant with coronavirus disease 2019 (COVID-19) had persistently positive nasopharyngeal swabs up to day 16 of admission. This case highlights the difficulties in establishing the true incidence of COVID-19, as asymptomatic individuals can excrete the virus. These patients may play important roles in human-to-human transmission in the community.


Why -aVF can be used in STAN as a proxy for scalp electrode-derived signal; reply to comments by Kjellmer et al.
The conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosén. These comments can be summarized as follows: 1) STAN analysis is based on a unipolar lead but the authors used a negative aVF lead, and they did not validate this methodology; 2) The fetuses used in the study were too young to display the signals that the authors were trying to detect. In response to these comments we now provide both a theoretical and an experimental underpinning of our approach. In an in vivo experiment in human we placed several electrodes over the head (simulating different places of a scalp electrode), simultaneously recorded Einthoven lead I and II, and constructed -aVF from these two frontal leads. Irrespective of scalp electrode placement, the correlation between any of unipolar scalp electrode-derived signals and constructed-aVF was excellent (≥ 0.92). In response to the second comment we refer to a study which demonstrated that umbilical cord occlusion resulted in rapid increase in T/QRS ratio that coincided with initial hypertension and bradycardia at all gestational ages which were tested from 0.6-0.8 gestation. The animals of our study were in this gestational range and, hence, our experimental setup can be used to assess STAN's quality to detect fetal hypoxia. In conclusion, we have clearly demonstrated the appropriateness of using-aVF as a proxy for a scalp electrode-derived signal in STAN in these preterm lambs. Investigation why STAN could not detect relevant ST-changes and instead produced erroneous alarms in our experimental setup is hampered by the fact that the exact STAN algorithm (signal processing and analysis) is not in the public domain.


[Effect of support removal on pre-saccadic EEG potentials in test-subjects with various asymmetry profiles].
Saccades and slow pre-saccadic potentials were investigated in 12 volunteered test-subjects (7 subjects with the leading right eye (RE-group) and 5 subjects with the leading left eye (LE-group) before and after 6-d DI experiment. Visual stimulation was provided with 3 LEDs one of which was located centrally in the field of vision and the other two - 10 degrees left and right along the horizontal axis. The subjects performed the test for antisaccades requiring to produce saccades toward a point symmetrical to displayed stimulus. EEG (monopolar in 19 standard leads) and electrooculogram were registered. Peripheral stimulus activation served as a trigger for backward averaging as a method to obtain slow pre-saccadic potentials (PSPs). Testing before immersion did not reveal any noteworthy differences in saccades produced by the members of both groups. At the same time, amplitude of pre-saccadic negativity (PSN) in LE-group was lower, especially in the frontal region of head, and distinguished by apparent asymmetry throughout the period of analysis. In immersion, latent saccades and percentage of erroneous reactions did not change in the RE-group but increased in the LE-group. Both groups reduced the PSN amplitudes shifting PSN to the right cerebral hemisphere; differences between the groups were masked by immersion. The RE-group was marked by a reliable decline of the PSN amplitude in the frontal leads due to, probably, sensory disintegration and reduced tonic afferentation in immersion. In the LE-group, maximum PSN amplitude was registered in the central region of head equally before and during immersion.


Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome.
The utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet. A retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated. Plasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them. Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.


[Regional differentiation of demographic dynamics in Russia and the role of healthcare].
The article examines the role of the processes of natural and migration movement of the population in changing the total population of the regions of Russia for more than two decades of the XXI century. Six possible combinations of these processes are proposed, which result in either an overall increase in the population or a reduction. During the period under review, various scenarios in a number of regions had fairly stable trends - a constant decline in the population or a stable increase in it. Moreover, such stability was determined either by a stable natural increase exceeding the migration decline, or by a stable decrease in the population as a result of a stable natural decline or migration outflow. But many regions experienced both the turbulence of reproduction and migration processes, as a result of which the overall result for population dynamics also changed. For the first time, a typology of Russian regions was carried out according to the frequency of the influence of natural and migration growth on the total population of the regions. This allowed further studies to consider the role of migration processes on the demographic aging of the population of the regions.


RBM47 is a Critical Regulator of Mouse Embryonic Stem Cell Differentiation.
RNA-binding proteins (RBPs) are pivotal for regulating gene expression as they are involved in each step of RNA metabolism. Several RBPs are essential for viable growth and development in mammals. RNA-binding motif 47 (RBM47) is an RRM-containing RBP whose role in mammalian embryonic development is poorly understood yet deemed to be essential since its loss in mouse embryos leads to perinatal lethality. In this study, we attempted to elucidate the significance of RBM47 in cell-fate decisions of mouse embryonic stem cells (mESCs). Downregulation of Rbm47 did not affect mESC maintenance and the cell cycle but perturbed the expression of primitive endoderm (PrE) markers and increased GATA4 + PrE-like cells. However, the PrE misregulation could be reversed by either overexpressing Rbm47 or treating the knockdown mESCs with the inhibitors of FGFR or MEK, suggesting an implication of RBM47 in regulating FGF-ERK signaling. Rbm47 knockdown affected the multi-lineage differentiation potential of mESCs as it regressed teratoma in NSG mice and led to a skewed expression of differentiation markers in serum-induced monolayer differentiation. Further, lineage-specific differentiation revealed that Rbm47 is essential for proper differentiation of mESCs towards neuroectodermal and endodermal fate. Taken together, we assign a hitherto unknown role(s) to RBM47 in a subtle regulation of mESC differentiation.


Is the eye-movement field confused about fixations and saccades? A survey among 124 researchers.
Eye movements have been extensively studied in a wide range of research fields. While new methods such as mobile eye tracking and eye tracking in virtual/augmented realities are emerging quickly, the eye-movement terminology has scarcely been revised. We assert that this may cause confusion about two of the main concepts: fixations and saccades. In this study, we assessed the definitions of fixations and saccades held in the eye-movement field, by surveying 124 eye-movement researchers. These eye-movement researchers held a variety of definitions of fixations and saccades, of which the breadth seems even wider than what is reported in the literature. Moreover, these definitions did not seem to be related to researcher background or experience. We urge researchers to make their definitions more explicit by specifying all the relevant components of the eye movement under investigation: (i) the oculomotor component: e.g. whether the eye moves slow or fast; (ii) the functional component: what purposes does the eye movement (or lack thereof) serve; (iii) the coordinate system used: relative to what does the eye move; (iv) the computational definition: how is the event represented in the eye-tracker signal. This should enable eye-movement researchers from different fields to have a discussion without misunderstandings.


On-column 2p bound state with topological charge ±1 excited by an atomic-size vortex beam in an aberration-corrected scanning transmission electron microscope.
Atomic-size vortex beams have great potential in probing the magnetic moment of materials at atomic scales. However, the limited depth of field of vortex beams constrains the probing depth in which the helical phase front is preserved. On the other hand, electron channeling in crystals can counteract beam divergence and extend the vortex beam without disrupting its topological charge. Specifically, in this article, we report that atomic vortex beams with topological charge ±1 can be coupled to the 2p columnar bound states and propagate for more than 50 nm without being dispersed and losing its helical phase front. We give numerical solutions to the 2p columnar orbitals and tabulate the characteristic size of the 2p states of two typical elements, Co and Dy, for various incident beam energies and various atomic densities. The tabulated numbers allow estimates of the optimal convergence angle for maximal coupling to 2p columnar orbital. We have also developed analytic formulae for beam energy, convergence angle, and hologram-dependent scaling for various characteristic sizes. These length scales are useful for the design of pitch-fork apertures and operations of microscopes in the vortex-beam imaging mode.


Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system.
In this study, we focused on the pharmacological characterization of cannabinoid receptor coupling to G protein-gated inwardly rectifying potassium (GIRK) channels. Cannabinoids were tested on Xenopus laevis oocytes coexpressing the CB(1) receptor and GIRK1 and GIRK4 channels (CB(1)/GIRK1/4) or the CB(2) receptor and GIRK1/4 channels (CB(2)/GIRK1/4). WIN 55,212-2 enhanced currents carried by GIRK channels in the CB(1)/GIRK1/4 and CB(2)/GIRK1/4 system; however, the CB(2) receptor did not couple efficiently to GIRK1/4 channels. In the CB(1)/GIRK1/4 system, WIN 55,212-2 was the most efficacious compound tested. CP 55,940 and anandamide acted as partial agonists. The rank order of potency was CP 55,940 > WIN 55,212-2 = anandamide. The CB(1)-selective antagonist SR141716A alone acted as a inverse agonist by inhibiting GIRK currents in oocytes expressing CB(1)/GIRK1/4, suggesting the CB(1) receptor is constitutively activated. A conserved aspartate residue, which was previously shown to be critical for G protein coupling in cannabinoid receptors, was mutated (to asparagine, D163N) and analyzed. Oocytes coexpressing CB(1)/GIRK1/4 or D163N/GIRK1/4 were compared. The potency of WIN 55, 212-2 at the mutant receptor was similar to wild type, but its efficacy was substantially reduced. CP 55,940 did not elicit currents in oocytes expressing D163N/GIRK1/4. In summary, it appears the CB(1) and CB(2) receptors couple differently to GIRK1/4 channels. In the CB(1)/GIRK1/4 system, cannabinoids evaluated demonstrated the ability to enhance or inhibit GIRK currents. Furthermore, a conserved aspartate residue in the CB(1) receptor is required for normal communication with GIRK channels in oocytes demonstrating the interaction between receptor and channels is G protein dependent.


GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer.
Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived "colonosphere" cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis, and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multilineage differentiation, proliferation, and tumor growth without reducing the tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively correlated with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity, but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity.


[Efficiency of color vision tests in hereditary dyschromatopsia: case report].
The authors describe two cases of hereditary dyschromatopsia and discuss the efficiency of the color vision tests. The patients were disapproved in different federal public examinations because Ishihara's test diagnosed hereditary dyschromatopsia. Ophthalmological evaluation was normal. No symptoms related to dyschromatopsia were presented. Panels D15 and Roth D 28 were normal. Desaturated D 15 showed deuteranomaly in case one. In the second case the comparative color vision tests showed nonspecific disorder. The diagnosis of dyschromatopsia is complex. The authors recommend comparative color vision tests to complement the Ishihara test for a better understanding of the color deficiency.


A model-constrained Monte Carlo method for blind arterial input function estimation in dynamic contrast-enhanced MRI: I. Simulations.
Widespread adoption of quantitative pharmacokinetic modeling methods in conjunction with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has led to increased recognition of the importance of obtaining accurate patient-specific arterial input function (AIF) measurements. Ideally, DCE-MRI studies use an AIF directly measured in an artery local to the tissue of interest, along with measured tissue concentration curves, to quantitatively determine pharmacokinetic parameters. However, the numerous technical and practical difficulties associated with AIF measurement have made the use of population-averaged AIF data a popular, if sub-optimal, alternative to AIF measurement. In this work, we present and characterize a new algorithm for determining the AIF solely from the measured tissue concentration curves. This Monte Carlo blind estimation (MCBE) algorithm estimates the AIF from the subsets of D concentration-time curves drawn from a larger pool of M candidate curves via nonlinear optimization, doing so for multiple (Q) subsets and statistically averaging these repeated estimates. The MCBE algorithm can be viewed as a generalization of previously published methods that employ clustering of concentration-time curves and only estimate the AIF once. Extensive computer simulations were performed over physiologically and experimentally realistic ranges of imaging and tissue parameters, and the impact of choosing different values of D and Q was investigated. We found the algorithm to be robust, computationally efficient and capable of accurately estimating the AIF even for relatively high noise levels, long sampling intervals and low diversity of tissue curves. With the incorporation of bootstrapping initialization, we further demonstrated the ability to blindly estimate AIFs that deviate substantially in shape from the population-averaged initial guess. Pharmacokinetic parameter estimates for K(trans), k(ep), v(p) and v(e) all showed relative biases and uncertainties of less than 10% for measurements having a temporal sampling rate of 4 s and a concentration measurement noise level of sigma = 0.04 mM. A companion paper discusses the application of the MCBE algorithm to DCE-MRI data acquired in eight patients with malignant brain tumors.


A partial chromosomal deletion caused by random plasmid integration resulted in a reduced virulence phenotype in Fusarium graminearum.
Fusarium graminearum (teleomorph: Gibberella zeae) is an Ascomycete fungal plant pathogen which infects a range of agriculturally important crops, including wheat, barley, and maize. A random plasmid insertion mutagenesis approach was used to analyze the pathogenicity of the PH-1 strain, for which full genomic information is available. Fungal transformants were initially screened for their ability to infect wheat ears. From a total of 1,170 transformants screened, eight were confirmed to be highly reduced in pathogenicity toward wheat ears and roots. These were designated disease-attenuated F. graminearum (daf) mutants. The in vitro growth rate and appearance of each daf mutant was equivalent to the parental strain. Deoxynivalenol (DON) was not detected in threshed grain recovered from ears inoculated with the daf10 mutant. Plasmid rescue and sequencing of the mutant daf10 revealed a deletion of approximately 350 kb from one end of chromosome 1. This chromosome segment is predicted to contain 146 genes. Microarray analysis of daf10 gene expression during growth in DON-inducing conditions confirmed the large deletion. The identities of the genes deleted and their potential role in DON production, pathogenesis, and other life processes are discussed.


Pattern formation in plastic liquid films on elastomers by ratcheting.
Plastic liquids, also known as Bingham liquids, retain their shape when loads are small, but flow when loads exceed a threshold. We discovered that plastic liquid films coated on elastomers develop wavy patterns under cyclic loads. As the number of cycles increases, the wavelength of the patterns remains unchanged, but the amplitude of the patterns increases and then saturates. Because the patterns develop progressively under cyclic loads, we call this phenomenon as "patterning by ratcheting". We observe the phenomenon in plastic liquids of several kinds, and studied the effects of thickness, the cyclic frequency of the stretch, and the range of the stretch. Finite element simulations show that the ratcheting phenomenon can occur in materials described by a commonly used model of elastic-plastic deformation.


[Restoration of the behavioral reactions of Rana esculenta frogs during regeneration of visual nerve fibers].
After sectioning the optic nerve, various forms of visually guided behaviour in the frog R. esculenta recover unevenly. Within 16--20 days, the onset of reactions was observed which are associated with perception of relatively large unmoving objects during active locomotion of animals (1); within 55 days -- avoidance reactions (2); within 90 days -- feeling reactions (3) were formed. In electrophysiological experiments it was shown that axons of the ganglionic retinal cells from various classes form contacts with the tectum also at different periods. The data obtained confirm the significance of specialized "canalization" of the retino--central nervous systems of transmission and evaluation of visual information for organization of separate forms of visually monitored behaviour in frogs.


Adefovir-induced Stevens-Johnson syndrome and toxic epidermal necrolysis overlap syndrome.
An increasing number of patients with chronic hepatitis B infection are being treated with the newly licensed drug, adefovir. It is an acyclic nucleoside phosphonate that is relatively safe in the dosage generally used for chronic hepatitis B. Serious adverse cutaneous drug reactions like Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) following adefovir use have not been reported. We report a case of adefovir-induced SJS and TEN overlap syndrome in a patient with chronic hepatitis B infection.


Trends in low birthweight among the Bhutanese refugee population in Nepal.
Although much is known about risk factors for low birthweight, an important cause of neonatal death, little is known about how to reduce or prevent low birthweight. This study aimed to verify a low rate in the incidence of low birthweight reported in the Bhutanese refugee camps in Nepal and, if true, to try to understand how this came about. Medical records from 1994 to 2001 were recovered for half of the refugee population, and birthweight and other maternal factors were analyzed. The adequacy of the food ration provided to the general population was assessed by comparing it with the nutrient requirements of pregnant women. The rates of low birthweight were indeed low in the refugee camps, averaging 11% in the years reviewed. Between 1996 and 1998, the mean rate of low birthweight fell from 16% to 8% and mean birthweight increased from 2.84 kg (SE, 2.80-2.87) to 3.0 kg (SE, 2.97-3.03). The increase in birthweight occurred following improvements in the micronutrient-to-energy ratios of the general ration. Rates of low birthweight comparable to those in developed countries were achieved in an ethnic Nepali population within 5 years of settlement in refugee camps. These low rates were probably achieved because basic needs of mothers were met, including both the quantity and the micronutrient content of food, water and sanitation, antenatal care, and education. The improvement from 1996 to 1998 coincided with increased availability of micronutrients in the food ration. We hypothesize that increased periconceptional micronutrient intake may be responsible for the increase in birthweight.


Insomnia subtypes characterised by objective sleep duration and NREM spectral power and the effect of acute sleep restriction: an exploratory analysis.
Insomnia disorder (ID) is a heterogeneous disorder with proposed subtypes based on objective sleep duration. We speculated that insomnia subtyping with additional power spectral analysis and measurement of response to acute sleep restriction may be informative in overall assessment of ID. To explore alternative classifications of ID subtypes, insomnia patients (n = 99) underwent two consecutive overnight sleep studies: (i) habitual sleep opportunity (polysomnography, PSG) and, (ii) two hours less sleep opportunity (electroencephalography, EEG), with the first night compared to healthy controls (n = 25). ID subtypes were derived from data-driven classification of PSG, EEG spectral power and interhemispheric EEG asymmetry index. Three insomnia subtypes with different sleep duration and NREM spectral power were identified. One subtype (n = 26) had shorter sleep duration and lower NREM delta power than healthy controls (short-sleep delta-deficient; SSDD), the second subtype (n = 51) had normal sleep duration but lower NREM delta power than healthy controls (normal-sleep delta-deficient; NSDD) and a third subtype showed (n = 22) no difference in sleep duration or delta power from healthy controls (normal neurophysiological sleep; NNS). Acute sleep restriction improved multiple objective sleep measures across all insomnia subtypes including increased delta power in SSDD and NSDD, and improvements in subjective sleep quality for SSDD (p = 0.03), with a trend observed for NSDD (p = 0.057). These exploratory results suggest evidence of novel neurophysiological insomnia subtypes that may inform sleep state misperception in ID and with further research, may provide pathways for personalised care.


Uterine Artery Embolization as an Effective Management and Diagnostic Tool for Puerperal Uterine Inversion with Severe Postpartum Bleeding: A Case Report.
Acute puerperal uterine inversion is a rare postpartum obstetric complication; however, without rapid diagnosis and appropriate management, it is life-threatening. Substantial bleeding hinders the verification of a partially inverted uterus, possibly delaying the treatment. Herein, we present the report of a 32-year-old female presenting with massive postpartum bleeding managed by uterine artery embolization. The peculiar course of the uterine artery bowing inferiorly along the inverted fundus during embolization could uncover the uterine inversion, which was not diagnosed by physical examination and CT. In conclusion, uterine artery embolization is not only an effective therapeutic strategy for postpartum hemorrhage but also a valuable tool for diagnosing uterine inversion.


Development of a cell with dendritic morphology from a precursor of B lymphocyte lineage.
Cells developing dendritic morphology were detected in cultures of highly purified human B cells incubated with 4 beta-phorbol 12-myristate 13-acetate (PMA). After 72 hr of culture, 2 to 7% of the cells had assumed a dendritic shape provided that contact with a plastic or glass surface also occurred. Dendritic cells developed in cultures of B cells prepared by positively selecting cells that stained with the B cell-specific monoclonal antibody B1 with the fluorescence-activated cell sorter. By contrast, dendritic cells could not be detected in cultures of cells obtained from patients with Bruton's type agammaglobulinemia that lacked B cells. Cells with dendritic morphology were nonspecific esterase negative and not phagocytic. They expressed HLA-DR, DQ, and DP antigens, receptors for interleukin 2 and transferrin, and were stained by B1 and 60.3, an antibody that identifies the beta-chain common to lymphocyte function associated antigen-1, complement receptor 3, and the p150,95 antigen, but not by monoclonal antibodies to monocytes, complement receptors 2 or 3, NK cells, T cells, or Langerhans' cells. Formation of dendritic cells was inhibited by microtubule poisons (vinblastine, colchicine), a microfilament inhibitor (cytochalasin B), and the 60.3 monoclonal antibody, but not by inhibition of DNA synthesis. These data indicate that a subset of B cells is capable of assuming dendritic morphology after stimulation with phorbol esters and attachment to a surface. These dendritic cells exhibit characteristics that are quite similar to the interdigitating cells found in T cell-dependent areas of lymph nodes.


Early versus delayed coronary artery bypass graft surgery for patients with non-ST elevation myocardial infarction.
Although coronary artery bypass graft surgery (CABG) has been proven to have mortality and morbidity benefits in patients with non-ST elevation myocardial infarction and multivessel disease, the appropriate timing of this procedure remains unclear. Therefore, we proposed a propensity score-matched analysis comparing the clinical outcomes between patients who underwent CABG within the first 48 h of admission (early CABG) and patients who underwent CABG after 48 h of admission (delayed CABG). Using the largest inpatient care database in the USA, the Nationwide Inpatient Sample, we identified patients with a primary diagnosis of acute myocardial infarction using the ICD 9-DM diagnosis codes. We then performed propensity score-matching analysis to control for 24 possible confounders. We identified 31 969 patients in the Nationwide Inpatient Sample database with a primary diagnosis of acute myocardial infarction who underwent CABG. The mean age of the cohort was 64.5±11.5 years and 33.4% were female. After performing propensity-matching analysis, we obtained a subset of 1555 patients in each group, with a mean age of 64.7±10.1 years; the male to female ratio was ~4 : 1. The incidence of hemorrhage, shock, and cardiac, pulmonary, and renal complications was comparable between the two groups. The incidence of mortality was not statistically significant between the two groups (2% in the early CABG vs. 1.8% in the delayed CABG, P=0.695). The mortality risk factors were as follows: age more than 70 years [odds ratio (OR): 3.42, 95% confidence interval (CI): 1.85-6.34, P<0.001]; cardiogenic shock (OR: 3.22, 95% CI: 1.35-7.67, P=0.008); and mechanical circulatory support with balloon counterpulsation (OR: 2.93, 95% CI: 1.45-5.90, P=0.003). CABG performed within 48 h of admission does not significantly increase the risk for in-hospital mortality compared with undergoing the procedure after 48 h of admission in propensity-matched patients.


Biomarker-driven patient selection for early clinical trials.
In this study we describe a new trend in biomarker-driven early drug development using enrichment and prescreening strategies. Technical and logistical obstacles that may hinder progress of this approach will be discussed, along with the ethical and financial concerns. Advances in tumor biology and human genetics with the identification of driver events and critical dependencies together with the development of drugs for specific targets hold promise for an era of personalized oncology treatment. Phase I trials provide an arena for early hypothesis testing, examining not only safety and toxicity, but also target engagement, biologically effective dosages, and the appropriate patient population. Integrating biomarker development into the early testing of novel agents might provide clinically relevant therapeutic opportunities for patients with advanced-stage cancer and also accelerate the drug approval process. After recent success stories with therapies targeting driver molecular aberrations in genetically defined tumor subtypes, innovative trials based on strong biological hypotheses are expected to bring further excitement to the field. Tumor heterogeneity and clonal evolution of the diverse populations of cancer cells during cancer progression, influenced by the effects of systemic treatments, will have to be taken into consideration in the scenario of drug development.


High Accuracy and Safety of Intraoperative CT-Guided Navigation for Transpedicular Screw Placement in Revision Spinal Surgery.
Intraoperative CT-guided navigation (iCT-navigation) has been reported to improve the accuracy and safety of transpedicular screw placement in primary spinal surgery. However, due to a disrupted bony anatomy and scarring tissue, revision spinal surgery can be challenging. The purpose of this study was to evaluate the accuracy and safety of iCT-navigation for screw placement at the virgin site versus the revision site in revision thoracolumbar spinal surgery. In total, 254 screws were inserted in 27 revision surgeries, in which 114 (44.9%) screws were inserted at the site with previous laminectomy or posterolateral fusion (the revision site), 64 (25.2%) were inserted at the virgin site, and 76 (29.9%) were inserted to replace the pre-existing screws. CT scans were conducted for each patient after all screws were inserted to intraoperatively confirm the screw accuracy. In total, 248 (97.6%) screws were considered accepted. The rate of accepted screws at the virgin site was 98.4% (63/64) versus 95.6% (109/114) at the revision site (p: 0.422). There were six (2.4%) unaccepted screws, which were immediately revised during the same operation. There was no neurological injury noted in our patients. With the use of iCT-navigation, the rate of accepted screws at the revision site was found to be comparable to that at the virgin site. We concluded that iCT-navigation could achieve high accuracy and safety for transpedicular screw placement in revision spinal surgery and allow for the immediate revision of unaccepted screws.


An autophosphorylation site database for leucine-rich repeat receptor-like kinases in Arabidopsis thaliana.
Leucine-rich repeat receptor-like kinases (LRR RLKs) form a large family of plant signaling proteins consisting of an extracellular domain connected by a single-pass transmembrane sequence to a cytoplasmic kinase domain. Autophosphorylation on specific Ser and/or Thr residues in the cytoplasmic domain is often critical for the activation of several LRR RLK family members with proven functional roles in plant growth regulation, morphogenesis, disease resistance, and stress responses. While identification and functional characterization of in vivo phosphorylation sites is ultimately required for a full understanding of LRR RLK biology and function, bacterial expression of recombinant LRR RLK cytoplasmic catalytic domains for identification of in vitro autophosphorylation sites provides a useful resource for further targeted identification and functional analysis of in vivo sites. In this study we employed high-throughput cloning and a variety of mass spectrometry approaches to generate an autophosphorylation site database representative of more than 30% of the approximately 223 LRR RLKs in Arabidopsis thaliana. We used His-tagged constructs of complete cytoplasmic domains to identify a total of 592 phosphorylation events across 73 LRR RLKs, with 497 sites uniquely assigned to specific Ser (268 sites) or Thr (229 sites) residues in 68 LRR RLKs. Multiple autophosphorylation sites per LRR RLK were the norm, with an average of seven sites per cytoplasmic domain, while some proteins showed more than 20 unique autophosphorylation sites. The database was used to analyze trends in the localization of phosphorylation sites across cytoplasmic kinase subdomains and to derive a statistically significant sequence motif for phospho-Ser autophosphorylation.


Two-dimensional continuous extraction in multiphase lipid bilayers to separate, enrich, and sort membrane-bound species.
A new method is presented to separate, enrich, and sort membrane-bound biomolecules based on their affinity for different coexisting lipid phases in a supported lipid bilayer using a two-dimensional, continuous extraction procedure. Analogous to classic liquid-liquid phase extraction, we created two distinct lipid phases in our planar membrane system: a liquid-ordered (l(o)) phase and a liquid-disordered (l(d)) phase arranged in parallel stripes inside a microfluidic device. Membrane-bound biomolecules in an adjacent supported lipid bilayer are convected in plane along the microfluidic channel and brought into contact with a different lipid phase using hydrodynamic force. A mixture of two lipid species, a glycolipid and a phospholipid, with known affinities for the two lipid phases employed here are used to demonstrate continuous extraction of the lipid-microdomain preferring glycolipid to the lo phase, while the phospholipid remains primarily in the ld phase. In this demonstration, we characterize the performance of this affinity-based separation device by building models to describe the velocity profile and transport in the two-phase coexistent membrane. We then characterize the impact of residence time on the extraction yield of each species. This new procedure sorts membrane species on the basis of chemical properties and affinities for specific lipid phases within a membrane environment near physiological conditions, critical for extending this method to the separation of lipid-linked proteins and transmembrane proteins while minimizing denaturation. This platform could facilitate the separation and identification of lipid membrane domain residents, or the characterization of changes in membrane affinity due to post-translational modifications or environmental conditions.


Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units.
To evaluate the frequency of gastrointestinal complications (GICs) in a prospective cohort of critically ill patients receiving enteral nutrition and to assess its effect on nutrient administration and its relationship to the patient's outcome. Multicenter, prospective cohort study. Thirty-seven multidisciplinary intensive care units (ICUs) in Spain. Prospective cohort of 400 consecutive patients admitted to the ICU and receiving enteral nutrition. Noninterventional, follow-up study. Enteral nutrition-related GICs and their management were defined by consensus before data collection. A set of variables related to enteral nutrition administration and the presence of GICs was recorded. During the 1-month study period, 400 patients were enrolled, and a total of 3,778 enteral feeding days were analyzed. The mean time of enteral nutrition was 9.6+/-0.4 days. Mean elapsed time from ICU admission to the start of enteral feeding was 3.1+/-0.2 days. A total of 265 patients (66.2%) received a standard polymeric formula, and 132 (33.8%) received a disease-specific one. Enteral feeds were administered mainly through a nasogastric tube (91%). One or more GICs were presented by 251 patients (62.8%) during the feeding course. The frequency of each particular GIC was as follows: high gastric residuals, 39%; constipation, 15.7%; diarrhea, 14.7%; abdominal distention, 13.2%; vomiting, 12.2%; and regurgitation, 5.5%. Enteral nutrition withdrawal as a consequence of noncontrollable GICs occurred in 15.2% of patients. The volume ratio (expressed as the ratio between administered and prescribed volumes) was calculated daily and was used as an index of diet administration efficacy. Patients with GICs had a lower volume ratio than did patients without GICs (63.1+/-1.20% vs. 93.3+/-0.3%) (p < .001), a longer length of stay (20.6+/-1.2 vs. 15.2+/-1.3 days) (p < .01), and higher mortality (31% vs. 16.1%) (p < .001). The frequency of enteral nutrition-related GICs in critically ill patients is high. High gastric residuals is the most frequent GIC. These complications decreased nutrient intake and, if persistent, could expose the patients to undernutrition. Enteral feeding gastrointestinal intolerance seems to have an evolutive effect in prolonging the ICU stay and increasing patient mortality.


Simulation Analyses of tDCS Montages for the Investigation of Dorsal and Ventral Pathways.
Modulating higher cognitive functions like reading with transcranial direct current stimulation (tDCS) can be challenging as reading involves regions in the dorsal and ventral cortical areas that lie in close proximity. If the two pathways are stimulated simultaneously, the function of dorsal pathway (predominantly used for graphophonological conversion) might interfere with the function of the ventral pathway (used for semantics), and vice-versa. To achieve functional specificity in tDCS for investigating the two pathways of reading, it is important to stimulate each pathway per session such that the spread of current across the cortical areas due to the two montages has minimal overlap. The present study intends to achieve this by introducing a systematic approach for tDCS analysis. We employed the COMETS2 software to simulate 10 montage configurations (5 for each pathway) for three electrode sizes: 5 × 5, 3 × 3, and 5 × 7 cm2. This diversity in montage configuration is chosen since previous studies found the position and the size of anode and cathode to play an important role. The values of the magnitude of current density (MCD) obtained from the configuration were used to calculate: (i) average MCD in each cortical lobe, (ii) number of overlapping coordinates, and (iii) cortical areas with high MCD. The measures (i) and (iii) ascertained the current spread by each montage within a cortical lobe, and (ii) verified the overlap of the spread of current between a pair of montages. The analyses show that a montage using the electrode size of 5 × 5 cm2 with the anode at CP5 and cathode at CZ, and another with anode at TP7 and cathode at nape of the neck are optimal choices for dorsal and ventral pathways, respectively. To verify, we cross-validated the results with ROAST. This systematic approach was helpful in reducing the ambiguity of montage selection prior to conducting a tDCS study.


Energy versus centrality dependence of the jet quenching parameter [Formula: see text] at RHIC and LHC: a new puzzle?
The central goal of jet quenching studies in high-energy nuclear collisions is the characterization of those QCD medium properties that are accessible by these probes. Most of the discussion in the last years has been focused on the determination of the jet quenching parameter, [Formula: see text]. We present here an extraction of this parameter using data of inclusive particle suppression at RHIC and LHC energies for different centralities. Our approach consists in fitting a K factor that quantifies the departure of this parameter from an ideal estimate, [Formula: see text], where [Formula: see text] is determined by the local medium quantities as provided by hydrodynamical calculations. We find that this K factor is larger at RHIC than at the LHC, as obtained already in previous analyses, but, surprisingly, it is almost independent of the centrality of the collision. Taken at face value, the K factor would not depend on the local properties of the medium as energy density or temperature, but on global collision quantities such as the center of mass energy. This is a very intriguing, unexpected possibility for which we cannot yet provide a clear interpretation. We also comment on the limitations of the formalism that may affect this conclusion.


Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma.
High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a survival advantage of Zevalin-BEAM. However, a large randomized study comparing Bexxar-BEAM and rituximab-BEAM did not show any advantage. More studies are needed to establish the role and the dose of RIT given for ASCT.


The immune response against pre-S2-encoded peptides and human serum albumin during hepatitis B virus infection.
Serum antibodies to human serum albumin (HSA) and its receptor structures (pre-S2) on HBV/HBsAg particles of IgG class were measured in patients with naturally acquired immunity to hepatitis B, HBsAg carriers with chronic liver disease, 'healthy' symptomless HBsAg carriers and controls. ELISA systems in which serum samples were diluted in 0.05 M PBS to give low protein concentrations followed by incubation at 4 degrees C were used. Anti-HSA and anti-pre-S2 were produced in patients during the acute phase of hepatitis B infection but were short-lived. The antibodies were absent in 'healthy' symptomless HBsAg carriers but present in the majority of HBsAg carriers with major liver disease. These results indicate that humoral immune responses of IgG class, normally initiated during the acute phase of HBV infection against the host 'self'-component HSA and/or its receptor structures, are down-regulated by immunological mechanisms while continuous production of these antibodies is associated with the pathogenesis of chronic HBV-induced liver disease.


Recurrent pure mucinous carcinoma of the breast with mediastinal great vessel invasion: HER-2/neu confers aggressiveness.
Mucinous carcinoma of the breast, also known as colloid carcinoma, is a less common variant of breast cancer constituting less than five per cent of breast cancers. We report the case of a 42-year-old premenopausal female who presented with a palpable chest wall recurrence 4 years after simple mastectomy, axillary node dissection, and TRAM flap reconstruction for pure mucinous carcinoma. The recurrent neoplasm was a pure mucinous carcinoma and was found to be invading the mediastinum into the great vessels. The tumor was estrogen receptor positive, progesterone receptor negative, and HER-2/neu positive, which is an unusual finding for mucinous carcinoma. The fact that this tumor demonstrated HER-2/neu positivity may explain the uncharacteristic aggressive nature of this normally indolent type of breast tumor. To our knowledge, this is the first reported case of any mucinous breast cancer invading the mediastinal great vessels and its subsequent en-bloc resection.


Public Interest in Cognitive Impairment: An Analysis of the Top 50 Articles on Cognitive Impairment on Altmetric.
As the average life expectancy continues to increase, interest in cognitive impairment is increasing. Nowadays, as social media expands its reach, academic research is spreading through social media, changing the way and speed by which research is propagated and also who consumes this content. Therefore, using Altmetric, a new web-based set of metrics that analyzes the impact of content on social media platforms, we investigated the characteristics of influential research articles on the topic of cognitive impairment in social media. An Altmetric Explorer search was performed on May 25, 2018, to extract the following information: (i) journal name, (ii) journal impact factor (IF), (iii) year of publication, (iv) article topic, (v) article type, and (vi) cognitive impairment subtype. The journal "Neurology" was the most cited journal for cognitive impairment articles shared on social media. Among the various types of cognitive impairment, most articles were related to dementia (all subtypes), Alzheimer's disease, and aging. The most common article type was original scientific paper, especially cohort study. The most popular topic was the identification of protective or risk factors for cognitive impairment. The characteristics of articles with a high Altmetric Attention Score were somewhat different from those of articles with a high number of traditional citations. Social media had the disadvantage that it was difficult to verify the authenticity of the primary source in question, but the advantage was that it could immediately determine the trends regarding how information about that source was being shared and consumed. Therefore, it may be advisable to use Altmetric analysis in combination with traditional methods of evaluating the research articles to understand the dissemination of scientific research and to direct future research.


Kinetic assay for high-throughput screening of in vitro transthyretin amyloid fibrillogenesis inhibitors.
Stabilization of tetrameric transthyretin (TTR) by binding of small ligands is a current strategy aimed at inhibiting amyloid fibrillogenesis in transthyretin-associated pathologies, such as senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy (FAP). A kinetic assay is developed for rapid evaluation of compounds as potential in vitro inhibitors in a high-throughput screening format. It is based on monitoring the time-dependent increase of absorbance due to turbidity occurring by acid-induced protein aggregation. The method uses the highly amyloidogenic Y78F mutant of human transthyretin (heterogously expressed in Escherichia coli cells). Initial rates of protein aggregation at different inhibitor concentrations follow a monoexponential dose-response curve from which inhibition parameters are calculated. For the assay development, thyroid hormones and nonsteroidal antiinflamatory drugs were chosen among other reference compounds. Some of them are already known to be in vitro inhibitors of TTR amyloidogenesis. Analysis time is optimized to last 1.5 h, and the method is implemented in microtiter plates for screening of libraries of potential fibrillogenesis inhibitors.


Anemia management program reduces transfusion volumes, incidence of ventilator-associated pneumonia, and cost in trauma patients.
Strategies to restrict transfusions are gaining acceptance in critical care. We implemented an anemia management program (AMP) for trauma patients in the Surgical Intensive Care Unit. AMP was based on a transfusion trigger of 7 g/dL hemoglobin once hemodynamic sufficiency was achieved. We hypothesized that AMP would decrease the transfusion of packed red blood cells (PRBCs) and cost without detriment in clinical outcomes. Transfusion data were retrospectively collected for all trauma patients treated in our Surgical Intensive Care Unit between July 2002 and December 2003. AMP was implemented in a step-wise fashion during a 6-month period (January to June 2003). Data were compared for the 6-month period before (Group I, July to December 2002) and after (Group II, July to December 2003) complete AMP implementation. Blood transfusion volumes were compared using negative binomial regression. Clinical outcomes (length of stay [LOS], death, myocardial infarction [MI], and ventilator-associated pneumonia [VAP]) were compared using risk ratios. Age, sex, and injury severity score (ISS) were examined as potential confounders. In all, 514 trauma patients were treated during the study period (n = 270 in Group I and n = 244 in Group II). Group I and Group II were similar in age (mean: 43.6 versus 42.9) and ISS (mean: 18.3 versus 17.0). Mean PRBCs per patient transfused decreased from 23.1 units to 17.1 units (p = 0.057), reflecting a 22.5% reduction adjusted for confounders (p = 0.097). Outcome data revealed no differences in LOS (mean: 6.4 versus 5.9, p = 0.920), risk of death (4.1% versus 6.1%, p = 0.158), or MI (0.7% versus 0.8%, p = 0.974), but a significant reduction in the incidence of VAP (8.1% versus 0.8%, p = 0.002). Total PRBC cost decreased during the study period from 503,000 dollars to 397,000 dollars. An anemia management program appears to be safe when applied in the acute ICU phase of trauma care. Implementation of AMP in the ICU reduced the volume of PRBCs transfused with significant cost savings. No significant differences in length of stay, mortality rate, or MI rate were seen. The significant decrease in the rate of VAP requires further elucidation. Further long-term and larger studies are indicated.


Influence of elastin gene polymorphism on the elastin content of the aorta: A study in 2 strains of rat.
The elastin content in the thoracic aorta of male Brown-Norway (BN) rats is 31.4+/-1.2% (dry weight), whereas that of male LOU rats is 37.2+/-1.0%. A similar difference in the elastin content of the thoracic aorta is also observed in female animals. Furthermore, in the thoracic aorta of young, growing rats as well as in cultured aortic smooth muscle cells, the steady-state level of elastin mRNA is significantly lower in the BN than in the LOU strain. These results suggested that 1 or more genes control the elastin mRNA level and the elastin content in the aortas of BN and LOU rats. A possible relationship between a polymorphism in the elastin gene and the elastin content of the aorta was tested. For this purpose, the aortic elastin content was measured in F(1) and F(2) generations bred from LOU and BN rats and was compared with that of the F(0) (parental) generation. A polymorphic marker located in intron 25 of the elastin gene has been used to genotype the F(2) rats. The degree of genetic determination of aortic elastin content was estimated to be 73% in the F(2) cohort, but the elastin locus accounts for only 3. 9% of the total variance in aortic elastin content. Other genes are thus responsible for the major part of the observed interstrain difference by regulating the transcription of the gene, the stability of elastin mRNA, and/or posttranslational events.


Cholangiographic demonstration of relief of narcotic-induced spasm of the sphincter of Oddi.
Narcotics are known to cause spasm of the sphincter of Oddi. This spasm may be difficult to distinguish from obstruction of the distal common bile duct on operative cholangiograms in cases where narcotics are used perioperatively. A case is presented in which narcotic-induced spasm of the sphincter of Oddi, clearly demonstrated in an operative cholangiogram, is reversed by a narcotic antagonist, thereby avoiding an unnecessary common duct exploration.


Studies on human cataracts. I. Evaluation of techniques of human cataract preservation after extraction.
The effects of several media and temperatures on the features (i.e. classification) of human cataracts have been studied with the aim of defining those storage conditions that least alter the appearance of the cataract after extraction. It was found that distilled water, normal saline, TC 199 medium with extra bicarbonate and 5.5 mM glucose, and silicone oil at 4 degrees, 36 degrees, and 37 degrees C are all unsatisfactory for preserving cataracts for more than 1 hr. Normal saline and TC 199 medium with bicarbonate and glucose are satisfactory for period not exceeding 30 to 60 min at 4 degrees C. The best set of conditions, one that leads to no significant change in the appearance of the cataract, is storage in a small covered glass vial at 4 degrees C with no added fluid. In this moist chamber, no significant changes in cataract classification occurred during a 4 hr period. The effect of -20 degrees C for 15 min on the appearance of a nuclear cataract was negligible, and it was concluded that lenses so treated could be used for a correlation between the nuclear cataract's CCRG classification and its light scattering properties, as studied in Parts II and III.


The embryotoxicity of ytterbium chloride in golden hamsters.
Two experiments were performed to assess the embryotoxicity of intravenously administered ytterbium chloride in golden hamsters: (1) 50, 75, 100, or 150 mg/kg ytterbium chloride were injected early on the 8th gestation day; (2) 100 mg/kg ytterbium chloride were administered at 4 different times during the critical period of organogenesis in this species (7th day, 4 PM; 8th day, 8 AM or 4 PM; 9th day, 8 AM). The pregnant females were killed on the 12th, 14th, or 15th gestation day and the frequency of resorptions was determined, and surviving offspring were studied for the presence of external and internal malformations as well as skeletal damage. Relatively few externally visible malformations and no significant internal malformations were produced. Damage to the skeletal system included fused and supernumerary ribs, and many different sites of poor ossification. Maximal susceptibility to these effects occurred on the 8th day.


Characteristics of First Recovery Step Response following Unexpected Loss of Balance during Walking: A Dynamic Approach.
Many falls in older adults occur during walking and result in lateral falls. The ability to perform a recovery step after balance perturbation determines whether a fall will occur. To investigate age-related changes in first recovery step kinematics and kinematic adaptations over a wide range of lateral perturbation magnitudes while walking. Thirty-five old (78.5 ± 5 years) and 19 young adults (26.0 ± 0.8 years) walked at their preferred walking speed on a treadmill. While walking, the subjects were exposed to announced right/left perturbations in different phases of the gait cycle that were gradually increased in order to trigger a recovery stepping response. The subjects were instructed to react naturally and try to avoid falling. Kinematic analysis was performed to analyze the first recovery step parameters (e.g., step initiation, swing duration, step length, and the estimated distance of the center of mass from the base of support [dBoS]). Compared with younger adults, older adults displayed a significantly lower step threshold and at lower perturbation magnitudes during the experiment. Also, they showed slower compensatory step initiation, shorter step length, and dBoS with similar step recovery times. As the perturbation magnitudes increased, older adults showed very small, yet significant, decreases in the timing of the step response, and increased their step length. Younger adults did not show changes in the timing of stepping, with a tendency toward a significant increase in step length. First compensatory step performance is impaired in older adults. In terms of the dynamic approach, older adults were more flexible, i.e., less automatic, while younger adults displayed more automatic behavior.


Soluble HTLV-I Tax1 protein stimulates proliferation of human peripheral blood lymphocytes.
Human T-cell leukemia virus type I (HTLV-I) is associated with two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). Lymphocytes from patients with ATL or TSP/HAM display abnormal proliferation properties in culture. Here we report that purified, soluble Tax1 protein can be taken up by, and stimulate proliferation of, uninfected human peripheral blood lymphocytes (PBLs) that have been stimulated with phytohemagglutinin (PHA). Tax1 was 40 to 70% as active as interleukin-2 (IL-2) in stimulating proliferation of PBLs. Heat inactivation, chloroform extraction, and immunoprecipitation with antisera specific for Tax1 each abolished the ability of the protein to stimulate lymphocyte proliferation. Tax1 failed to stimulate PBL proliferation in the absence of PHA. After an initial round of cell division, Tax1-treated PBLs exhibited prolonged sensitivity to IL-2-induced proliferation. These results indicate that Tax1 can stimulate lymphocyte proliferation in culture and imply that extracellular Tax1 may be involved in the spontaneous proliferation of TSP/HAM lymphocytes and the IL-2-dependent proliferation of ATL lymphocytes.


Universal inverse design of surfaces with thin nematic elastomer sheets.
Programmable shape-shifting materials can take different physical forms to achieve multifunctionality in a dynamic and controllable manner. Although morphing a shape from 2D to 3D via programmed inhomogeneous local deformations has been demonstrated in various ways, the inverse problem-finding how to program a sheet in order for it to take an arbitrary desired 3D shape-is much harder yet critical to realize specific functions. Here, we address this inverse problem in thin liquid crystal elastomer (LCE) sheets, where the shape is preprogrammed by precise and local control of the molecular orientation of the liquid crystal monomers. We show how blueprints for arbitrary surface geometries can be generated using approximate numerical methods and how local extrinsic curvatures can be generated to assist in properly converting these geometries into shapes. Backed by faithfully alignable and rapidly lockable LCE chemistry, we precisely embed our designs in LCE sheets using advanced top-down microfabrication techniques. We thus successfully produce flat sheets that, upon thermal activation, take an arbitrary desired shape, such as a face. The general design principles presented here for creating an arbitrary 3D shape will allow for exploration of unmet needs in flexible electronics, metamaterials, aerospace and medical devices, and more.


Anterior cingulate activity during routine and non-routine sequential behaviors in macaques.
Anterior cingulate cortex is important in monitoring action for new challenges. We recorded neuron activity in the anterior cingulate sulcus of macaques while they performed a sequential problem-solving task. By trial and error, animals determined the correct sequence for touching three fixed spatial targets. After the sequence was repeated three times, we then changed the correct solution order, requiring a new search. Irrespective of component movements or their kinematics, task-related neurons encoded the serial order of the sequence. Neurons activated with sequence components (68%) differed in activity between search and repetition. Search-related activity occurred when behavioral flexibility was required and ended as soon as the animal accumulated enough information to infer the solution, but had not yet tested it. Repetition-related activity occurred in a regime of memory-based motor performance in which attention to action is less necessary.


Simplified validated prognostic model for progression-free survival after autologous transplantation for hodgkin lymphoma.
Hodgkin lymphoma (HL) prognostic models based on factors measured at time of autologous hematopoietic cell transplantation (AHCT) are limited by small sample sizes. Models based on information at diagnosis are often not uniformly collected or available at transplantation. We propose an easily implementable prognostic model for progression-free survival (PFS) post-AHCT based on factors available at transplantation in a large international cohort of HL patients. The outcomes of 728 AHCT recipients for relapsed/refractory HL were studied. Patients were randomly selected for model development (n = 337) and validation (n = 391). The multivariate model identified 4 major adverse risk factors at the time of AHCT with the following relative weights: Karnofsky performance score <90 and chemotherapy resistance at AHCT were each assigned 1 point, whereas at least 3 chemotherapy regimens pre-AHCT and extranodal disease at AHCT were each assigned 2 points. Based on the total score summed for the 4 adverse risk factors, 3 risk groups were identified: low (score = 0), intermediate (score = 1 to 3), or high (score = 4 to 6). The 4-year PFS for the low- (n = 176), intermediate- (n = 261), and high- (n = 283) risk groups were 71% (95% confidence interval [CI], 63% to 78%), 60% (95% CI, 53% to 66%), and 42% (95% CI, 36% to 49%), respectively. The prognostic model was validated in an independent cohort. The Center for International Blood and Marrow Transplant Research model is based on factors easily available at the time of AHCT and discriminates patients with favorable post-AHCT outcomes as well as an intermediate-risk group. This model should assist in the prospective evaluation of alternative treatment strategies.


Identification of differentially regulated genes in fetal wounds during regenerative repair.
During mammalian skin development, wounds heal with regeneration rather than scar. Genomic microarray analysis of fetal (scarless) and postnatal (scarring) cutaneous wounds was performed to identify genes with differential expression and possible proregenerative function. Differentially expressed genes between the scarless and scarring wound transcriptomes were identified with significance analysis of microarrays. At early time points, the fraction of genes with increased expression was greater in the fetal wounds. Conversely, as time after injury increased, the fraction of genes with increased expression in postnatal wounds increased from 0% at 1 hour to 67% at 24 hours. The fetal 1- and 12-hour wound transcriptomes identified genes important in DNA transcription and repair, cell cycle regulation, protein homeostasis, and intracellular signaling. The predominant expression patterns of these genes from 1 to 24 hours predominantly revealed rapid up-regulation, followed by declining expression at 24 hours. Fewer genes with differential expression between the fetal scarless and postnatal scarring wound transcriptomes were identified at 24 hours, most of which had greater expression in the postnatal wound. Our data suggest that multiple gene products may be necessary for the coordination of skin regeneration during wound repair in the fetus.


[Problems of rheumatoid heart defects].
Of 160 patients with RA treated at the clinic recently, heart disease was diagnosed in 4. In 2 patients, mitral disease was recognized as rheumatic, in one patient, aortal disease was treated with a great probability as rheumatoid. In 4 patients, rheumatoid etiology of the disease was advanced and then was confirmed at autopsy. It is assumed that rheumatoid heart disease occurs more frequently than diagnosed.


Enrichment specificity of micro and nano-sized titanium and zirconium dioxides particles in phosphopeptide mapping.
Owning to their anion-exchange properties, titanium and zirconium dioxides are widely used in phosphopeptide enrichment and purification protocols. The physical and chemical characteristics of the particles can significantly influence the loading capacity, the capture efficiency and phosphopeptide specificity and thus the outcome of the analyses. Although there are a number of protocols and commercial kits available for phosphopeptide purification, little data are found in the literature on the choice of the enrichment media. Here, we studied the influence of particle size on the affinity capture of phosphopeptides by TiO2 and ZrO2. Bovine milk casein derived phosphopeptides were enriched by micro and nanoparticles using a single-tube in-solution protocol at different peptide-to-beads ratio ranging from 1 : 1 to 1 : 200. Unsupervised hierarchical cluster analysis based on the whole set of Matrix Assisted Laser Desorption/Ionization time-of-flight mass spectra of the phosphopeptide enriched samples revealed 62 clustered peptide peaks and shows that nanoparticles have considerably higher enrichment capacity than bulk microparticles. Moreover, ZrO2 particles have higher enrichment capacity than TiO2. The selectivity and specificity of the enrichment was studied by monitoring the ion abundances of monophosphorylated, multiphosphorylated and non-phosphorylated casein-derived peptide peaks at different peptide-to-beads ratios. Comparison of the resulting plots enabled the determination of the optimal peptide-to-beads ratios for the different beads studied and showed that nano-TiO2 have higher selectivity for phosphopeptides than nano-ZrO2 particles.


Comparison of RT-PCR assay and virus isolation in cell culture for the detection of Alkhumra hemorrhagic fever virus.
Alkhumra hemorrhagic fever virus (AHFV) is an emerging flavivirus that was isolated originally from Saudi Arabia in 1994-1995. The main tests used for the detection of AHFV are the real time (rt) RT-PCR and virus isolation in cell culture. In the present study the detection of AHFV by rtRT-PCR was compared with virus isolation in BHK-21, HEp-2, and LLC-MK2 cell lines. AHFV suspensions grown in BHK-21, HEp-2, and LLC-MK2 cell lines were serially diluted 10-fold from 10(-1) to 10(-11) . Samples from each dilution were used to inoculate four cell culture tubes and were also examined by the rtRT-PCR for AHFV RNA. Fifteen non-inoculated cell culture samples (five from each cell line) were included blindly in both tests. Thus, a total of 132 AHFV-positive and 15 negative control samples were tested. The rtRT-PCR could detect the viral RNA in all diluted specimens up to and including the 10(-10) dilution (40 specimens for each cell line), whereas, cell cultures were positive in 70% of specimens for BHK-21, 65% for LLC-MK2, and 45% for HEp-2 at this dilution. None of the three cell cultures nor the rtRT-PCR was positive at 10(-11) dilution. The specificity and positive predictive values of virus isolation compared to rtRT-PCR were each 100%, whereas the negative predictive values were 29.4% for BHK-21, 26.3% for LLC-MK2, and 18.5% for HEp-2. In conclusion, the rtRT-PCR is more sensitive than virus isolation for detecting AHFV.


The visible-light driven photocatalytic destruction of NO(x) using mesoporous TiO2 spheres synthesized via a "water-controlled release process".
Mesoporous anatase TiO2 spheres with tunable sizes ranging from 400 nm to 3 μm were synthesized using an original so-called "water-controlled solvothemal release process". In this method, the well-known esterification reaction between ethanol and acetic acid was creatively employed to generate water gradually during a solvothermal process. Thereafter, the slowly released water molecules functioned as nucleation centers for completing the hydrolysis of titanium tetraisopropoxide to produce homogenous mesoporous TiO2 spheres. In reality, these samples consisted of densely packed nanoparticles that formed spherical secondary particles with interparticle pores. Research has demonstrated that the diameter of the TiO2 spheres can be easily tuned by controlling the concentration of the Ti source in the starting solution. Regardless of their diameter, all of these TiO2 spheres exhibited a high specific surface area (above 150 m(2) g(-1)) originating largely from the contribution of mesopores. On the merits of their porous structure and related high specific surface area, the mesoporous TiO2 spheres showed a higher photocatalytic activity than P25 for the oxidative photo-destruction of NOx gas.


Camouflaging Cleft Lip Scar Using Follicular Unit Extraction Hair Transplantation Combined with Autologous Fat Grafting.
The scar that occurs after cleft lip surgery poses a serious cosmetic problem. One of the methods used to solve this problem in adult male patients is hair transplantation. However, satisfactory results with this method cannot always be achieved because of possible graft loss. The corrective feature of fat grafting has been reported in many studies. The authors' aim with this report is to share their results with hair transplantation combined with fat grafting in patients with cleft lip. This study included 20 patients who had both a scar and alopecia in the cleft lip area. The patients underwent fat grafting from the periumbilical region by means of miniature liposuction harvesting cannulas. Three months after fat injection, hair transplantation was performed with hair from the submental area and scalp using the folliculate unit extraction technique. Patients were followed for 12 months. Survival rate of transplanted hair and patient satisfaction were analyzed after the procedures. After this camouflaging technique with fat grafting and hair transplantation, the scar was hidden quite well. The graft survival rate was also better compared with results from similar studies. Patient and observer satisfaction results with the scar tissue were significantly improved, which was confirmed statistically. This study demonstrates that this combined camouflaging technique is a very effective treatment in male patients with cleft lip who have serious secondary upper lip scars. The authors present a series of patients treated with this technique, which resulted in a high level of patient satisfaction. Therapeutic, IV.


Evaluation of a universal hepatitis B vaccination program and antenatal screening for hepatitis B surface antigen: Results from a real-world study 2015-2016.
Universal vaccination against hepatitis B virus (HBV) in infancy was implemented in Israel in 1992. This population-based study aimed to evaluate the coverage rate and cost-benefit of the HBV vaccination program among infants in Israel and the Hepatitis B surface antigen (HBsAg) status in their mothers. Using the database of a health maintenance organization with 2 million members, we retrospectively identified, all the infants born in 2015-2016 and their mothers. Maternal data collected included age, ethnicity, country of birth and HBsAg status during pregnancy. HBV vaccination coverage among infants was calculated. A cost-benefit analysis of the HBV vaccination program was conducted based on the actual costs of HBV infection treatments in all HBsAg positive mothers. Our cohort included 72,792 mothers who gave birth to 77,572 live infants. A total of 71,107 (97.7%) mothers were screened for HBV during pregnancy, of them 124 (0.2%), who gave birth to 132 infants were HBsAg positive. HBV vaccination coverage rates were 94%, 93% and 89%, for the first, second and third dose, respectively. Birth dose coverage of 95% among infants born to HBsAg positive mothers was significantly higher compared to HBsAg negative or unscreened mothers (p < 0.001). The percentage of HBsAg positivity among mothers who were born in Israel, the Former Soviet Union or Ethiopia, were 0.1%, 0.8% and 5%, respectively (p < 0.001). Ethnic differences were not found between HBsAg positive and HBsAg negative mothers. Calculated benefit-to-cost ratios were 1.24:1 and 4.15:1, with and without antenatal HBsAg screening, respectively. The Israeli vaccination program against HBV infection is epidemiologically and economically justified. High coverage rates among infants born to HBsAg positive mothers reflect very good adherence to the vaccination program and antenatal screening. Higher HBsAg positivity rates among immigrant mothers identify a high-risk population for HBV infection.


Idiopathic chronic urticaria and celiac disease.
Idiopathic chronic urticaria (ICU) is a chronic relapsing cutaneous disease. Some case reports or studies on small series of celiac disease (CD) patients have suggested a possible association between CD and ICU. The aim of this study was to assess the prevalence of CD in a population of adults ICU patients with respect to healthy controls. We consecutively enrolled 80 patients affected by ICU and 264 blood donors as the control population without a history of ICU. Serum anti-transglutaminase IgG and anti-endomysium IgA antibodies were evaluated in all subjects. In the case of positivity to serology, diagnosis was confirmed by duodenal biopsy. One of 80 (1.25%) ICU patients were positive to both anti-transglutaminase and anti-endomysium antibodies. Duodenal biopsy showed partial villous atrophy. One control of 264 (0.38%) had CD. No statistical difference was found in the prevalence of CD between the two groups. ICU patients do not seem to bear a greater risk for CD compared to the general population.


Anthelmintic and metabolomic analyses of chicory (Cichorium intybus) identify an industrial by-product with potent in vitro antinematodal activity.
Chicory (Cichorium intybus) is a bioactive forage rich in sesquiterpene lactones (SLs) with reported in vitro and in vivo anthelmintic activity in livestock. However, the on-farm adoption of chicory as an anthelmintic crop is limited and may be facilitated by using standardised industrial chicory material. Chicory root pulp is a by-product obtained from industrial chicory roots after inulin extraction and can potentially retain SLs. However, SL content and associated anthelmintic activity of chicory root pulp have not been investigated. Here, we evaluated the anthelmintic activity of SL-enriched extracts from chicory root pulp and forage chicory, and used untargeted metabolomics and molecular networking to identify potential anthelmintic molecules. Six different sources of chicory material were used: fresh chicory root pulp (from industrial chicory roots C. intybus var. sativum; "Root Pulp"), fresh leaves from chicory cv. Spadona (sampled on four occasions) and fresh leaves from chicory cv. Choice. The resulting extracts were tested for anthelmintic activity against the free-living nematode Caenorhabditis elegans and the pig nematode Ascaris suum. The cytotoxicity of the chicory extracts was evaluated on mammalian (Vero) cells. In the C. elegans assays, the Root Pulp was the most potent extract and induced paralysis in >95% of worms exposed to >250 μg extract/mL (EC50 = 64.2 μg/mL). In the A. suum assays, the Root Pulp was also the most potent chicory extract to inhibit worm motility (EC50 = 87.6 μg/mL), followed closely by two of the Spadona leaf extracts (EC50 = 89.8 μg/mL and 112.2 μg/mL) The Root Pulp extract had the lowest cytotoxicity of all tested extracts towards mammalian cells, with a selectivity index of 5.37. Untargeted metabolomics revealed that chicory Root Pulp had a markedly different chemical profile in comparison with forage chicory extracts. Molecular networking confirmed several SLs and SL-derivatives mainly present in chicory root pulp, that may be responsible of its potent anti-parasitic activity. Bioactivity-based molecular networking of chicory root pulp and the most potent forage chicory extracts revealed a high predicted anthelmintic score for the guaianolide SL 11,13-dihydro-lactucopicrin. In conclusion, chicory root pulp showed potent and selective in vitro anthelmintic activity against C. elegans and A. suum, with low cytotoxicity in mammalian cells. The promising anthelmintic activity of chicory root pulp should be confirmed in vivo to further explore the potential of this agro-industrial by-product as a nutraceutical anthelmintic for livestock and as novel source of anti-parasitic compounds.


pH-Responsive Multifunctional Nanoplatforms with Reactive Oxygen Species-Controlled Release of CO for Enhanced Oncotherapy.
Recently, various nanomaterials have drawn increasing attention for enhanced tumor therapy. However, a lack of tumor uptake and insufficient generation of cytotoxic agents have largely limited the antitumor efficacy in vivo. Herein, a multifunctional nanoplatform (IL@CPPor(CO)) was constructed with pH-responsive copper peroxide nanoparticles (CPNP) that are capable of self-supplying H2O2, a radical-sensitive carbonic oxide (CO) donor (Fe3(CO)12), photosensitizer Iridium(III) meso-tetra (N-methyl-4-pyridyl)porphyrin pentachloride (IrPor), and ionic liquid (IL) for enhanced oncotherapy. Under acidic conditions, the CPNP could decompose to release H2O2 and Cu2+. The concomitant generation of H2O2 could efficiently trigger Fe3(CO)12 to release the CO in situ. On the other hand, Cu2+ possesses both glutathione depletion and Fenton-like properties. In addition, IrPor has both peroxidase-like activity and photosensitizer properties to produce reactive oxygen species (ROS) in tumors. The released ROS could trigger the rapid intracellular release of CO. More importantly, released CO and ROS could promote cell apoptosis and improve the therapeutic efficacy. Moreover, due to the pH-dependent ROS generation property, the IL@CPPor(CO) exhibited high tumor accumulation, low toxicity, and good biocompatibility, which enabled effective tumor growth inhibition with minimal side effects in vivo. This work provides a novel multifunctional nanoplatform that combined photodynamic therapy with CDT and CO to improve therapeutic efficacy.


Painting of fourth in genus Drosophila suggests autosome-specific gene regulation.
Painting of fourth (POF) is a chromosome-specific protein in Drosophila and represents the first example of an autosome-specific protein. POF binds to chromosome 4 in Drosophila melanogaster, initiating at the proximal region, followed by a spreading dependent on chromosome 4-specific sequences or structures. Chromosome-specific gene regulation is known thus far only as a mechanism to equalize the transcriptional activity of the single male X chromosome with that of the two female X chromosomes. In Drosophila, a complex including the male-specific lethal proteins, "paints" the male X chromosome, mediating its hypertranscription, explained to some extent by the acetylation of lysine 16 on histone H4. Here, we show that Pof is essential for viability in both sexes and for female fertility. POF binding to an autosome, the F element, is conserved in genus Drosophila, indicating functional conservation of the autosome specificity. In three of nine studied species, POF binds to the male X chromosome. When bound to the male X, it also colocalizes with the dosage compensation protein male-specific lethal 3, suggesting a relationship to dosage compensation. The chromosome specificity is determined at the species level and not by the amino acid sequence. We argue that POF is involved in a chromosome-specific regulatory function.


Understanding Chemoselectivity in Proton-Coupled Electron Transfer: A Kinetic Study of Amide and Thiol Activation.
While the mechanistic understanding of proton-coupled electron transfer (PCET) has advanced significantly, few reports have sought to elucidate the factors that control chemoselectivity in these reactions. Here we present a kinetic study that provides a quantitative basis for understanding the chemoselectivity in competitive PCET activations of amides and thiols relevant to catalytic olefin hydroamidation reactions. These results demonstrate how the interplay between PCET rate constants, hydrogen-bonding equilibria, and rate-driving force relationships jointly determine PCET chemoselectivity under a given set of conditions. In turn, these findings predict reactivity trends in a model hydroamidation reaction, rationalize the selective activation of amide N-H bonds in the presence of much weaker thiol S-H bonds, and deliver strategies to improve the efficiencies of PCET reactions employing thiol co-catalysts.


Virological and Immunological Status of the People Living with HIV/AIDS Undergoing ART Treatment in Nepal.
Antiretroviral therapy (ART) has increased the life span of the people living with HIV (PLHIV), but their virological and immunological outcomes are not well documented in Nepal. The study was conducted at a tertiary care center including 826 HIV-1 seropositive individuals undergoing ART for at least six months. Plasma viral load (HIV-1 RNA) was detected by Real Time PCR and CD4(+) T-lymphocyte (CD4(+)) counts were estimated by flow cytometry. The mean CD4(+) count of patients was 501 (95% CI = 325-579) cells/cumm, but about 35% of patients had CD4(+) T cell counts below 350 cells/cumm. With increasing age, average CD4(+) count was found to be decreasing (p = 0.005). Of the total cases, 82 (9.92%) were found to have virological failure (viral load: >1000 copies/ml). Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV), the frequently used ART regimen in Nepal, showed virological failure in 11.34% and immunological failure in 37.17% of patients. Virological failure rate was higher among children < 15 years (14.5%) (p = 0.03); however, no association was observed between ART outcomes and gender or route of transmission. The study suggests there are still some chances of virological and immunological failures despite the success of highly active ART (HAART).


Differential scanning calorimetry study of glass transition in frozen starch gels.
The effects of initial water content, maximum heating temperature, amylopectin crystallinity type, and annealing on the glass transition of starch gels were studied by differential scanning calorimetry (DSC). The glass transition temperatures of the frozen gels measured as the onset (T(g,onset)) or midpoint temperature (T(g,midpoint)), heat capacity change during the glass transition (deltaC(p)), unfrozen water of starch gels, and additional unfrozen water (AUW) arising from gelatinization were reported. The results show that T(g,onset) and T(g,midpoint) of the partially gelatinized gels are independent of the initial water content, while both of the T(g) values of the fully gelatinized gel increase as the initial water content increases. These observations might result from the difference in the level of structural disruption associated with different heating conditions, resulting in different gel structures as well as different concentrations of the sub-T(g) unfrozen matrix. The amylopectin crystallinity type does not greatly affect T(g,onset) and T(g,midpoint) of the gels. Annealing at a temperature near T(g,onset) increases both T(g,onset) and T(g,midpoint) of the gels, possibly due to an increase in the extent of the freeze concentration as evidenced by a decrease in AUW. Annealing results in an increase in the deltaC(p) value of the gels, presumably due to structural relaxation. A devitrification exotherm may be related to AUW. The annealing process decreases AUW, thus also decreasing the size of the exotherm.


Influence of host related factors on the antibody response to trivalent oral polio vaccine in Tunisian infants.
The low efficiency of trivalent oral polio vaccine (TOPV) in inducing protective antibody titres to polio3 is a problem of great importance in many regions of the world. A prospective study was conducted in 121 Tunisian infants aged 3 months during routine immunization with TOPV under carefully controlled conditions. Seroconversion rates to polio1, polio2 and polio3, one month after the third dose, were 94.7, 100 and 89.5%, respectively. The kinetics of the antibody response showed delayed and more difficult responses to polio3 compared to polio2 and polio1. The following host related factors, previously suggested to interfere with the immune response, were assessed: maternal antibodies; breast-feeding; concurrent enteric infections; and other illnesses. The main factor associated with the lack of seroconversion was concurrent infection with non-polio enteroviruses (NPE) which was found in 50% of non-responders to polio1 and/or to polio3 during the vaccination protocol whereas no NPE was isolated in vaccine responders. The other studied factors seemed not to interfere in the infants according to the locally adopted vaccination schedule and to the specific socio-economic conditions.


Granulomatous involvement of the liver in patients with AIDS.
During a one month period liver biopsy was carried out on eight patients with established acquired immune deficiency syndrome (AIDS) and two suspected of having AIDS to evaluate raised liver enzymes or unexplained fever and weight loss. Each of the 10 patients were found to have hepatic granulomas. Appropriate staining techniques showed acid-fast bacilli in seven of the liver specimens. One specimen contained numerous Cryptococcal organisms. Two biopsies showed granulomas but no organisms. Liver biopsy was found to be a high yield and rapid diagnostic procedure in patients with AIDS. Our results suggest that hepatic mycobacterial infection may be more common in the syndrome than previously recognised and that liver biopsy specimens should be examined routinely for the presence of acid-fast bacilli.