A cell-penetrating phospholamban-specific RNA aptamer enhances Ca2+ transients and contractile function in cardiomyocytes.
The sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a)-phospholamban (PLN) system of sarcoplasmic reticulum plays a pivotal role in regulation of intracellular Ca(2+) cycling in ventricular cardiomyocytes. Given that Ca(2+) cycling is impaired in heart failure, proteins that contribute to this process are potential targets for the treatment of this condition. We have now isolated PLN-specific aptamers with a phosphorothioate-modified backbone from a library of RNA molecules containing a randomized 40-nucleotide sequence by application of the systematic evolution of ligands by exponential enrichment (SELEX) protocol with a fusion protein containing the cytoplasmic region of human PLN. One of these aptamers was shortened to a 30-nucleotide oligomer (RNA-Apt30) without loss of function. RNA-Apt30 showed a high affinity for the cytoplasmic region of PLN (Kd=11 nM), but it did not bind to the phosphorylated form of PLN or to a phosphomimetic mutant. It also increased SERCA2a activity in isolated cardiac SR vesicles with an EC50 of 18 nM by relieving PLN-mediated inhibition. Conjugation of RNA-Apt30 to a cell-penetrating peptide allowed its delivery into adult rat cardiomyocytes, in which it enhanced both Ca(2+) transients and contractile function. These effects of the aptamer were also apparent in the presence of the β-adrenergic receptor antagonist propranolol. This cell-penetrating PLN aptamer may thus provide a basis for the development of new therapeutic agents for heart failure without the need for gene transfer or a change in endogenous protein expression.


Chart documentation by general physicians of the glaucoma medications taken by their patients.
To estimate the frequency of documentation of glaucoma medications by primary care physicians. Cross-sectional, observational study. The general medical records of 100 patients of one glaucoma specialist were reviewed. We recorded whether the mention of eyedrops appeared in the medical record. The median number of glaucoma medications used was 2.5 (range 1 to 5). Fifty-five (55%, 95% confidence interval: 45%-65%) of the medical records of the primary physicians mentioned eyedrops. Alpha-agonists were statistically less frequently documented (13%) in the general medical record than beta-adrenergic blockers (47%) and prostaglandins (44%). Almost half of the charts of these primary physicians had no documentation of any eyedrop use by their patients with glaucoma. An important step in reducing drug-induced side effects and interactions with other medications would be better recognition by primary physicians of the ophthalmic drugs used by their patients.


Validation of portal vein flow measurement by color flow Doppler sonography in a porcine model of septic shock.
To compare portal vein flow values gained by color flow Doppler sonography with simultaneously derived data from an ultrasound transit time flow probe. Repeated, simultaneous flow measurements were performed in a prospective study investigating the effect of various drugs on hepatosplanchnic perfusion and energy balance in a long-term model of stable, hyperdynamic endotoxin shock. Investigational animal laboratory. Domestic pigs. Alterations in respirator setting were studied with regard to their effect on the quality of color flow Doppler data in comparison to flow probe data. Additional experiments included variation in PEEP level in conjunction with volume resuscitation. Respiratory rates of 14-18/min led to color Doppler flow values consistently 20-40% above simultaneously measured flow probe data. Temporary apnea led to enhanced agreement of data. Reduction in respiratory rate to 8/min with increase in tidal volume consistently led to color Doppler data within 10% of the corresponding flow probe values. A short-term period of respirator-dependent, constant portal vein inflow enables color Doppler sonography to detect correct values in a clinically relevant setting of hyperdynamic endotoxin shock.


Theorems on log-convex disposition curves in drug and tracer kinetics.
Conventionally, analysis of the dynamic behaviour of substances in the whole organism is based on the multiexponential paradigm (compartmental model). Alternatively the use of power functions has been proposed. In this paper a unified view is developed investigating the implications of observed log-convexity of disposition (clearance) curves. Using a non-compartmental approach it is proved that the disposition residence time distribution corresponding to a log-convex impulse response (blood concentration-time curve) belongs to the DFR (decreasing failure rate) class, implying that (1) the disposition curve has an exponential tail and (2) the relative dispersion of residence times is greater than or equal to one. This class of disposition curves includes multiexponential and power functions as special cases. In terms of the underlying biophysical principles the DFR property is discussed as a consequence of a dominant role of passive distribution processes of particles in the organism. The paper also deals with the corresponding properties of a recirculatory model using renewal theoretic concepts.


A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years.
The purpose of this study was to investigate possible differences in the primary in situ cellular immune response between patients with and without relapse of Stage IB cervical squamous cell carcinoma. Paraffin-embedded tissue from 40 patients (20 with and 20 without relapse) was evaluated. Sections were immunostained for CD1a+, CD3+, CD4+, CD8+, CD20+, CD45RA+, CD45RO+, CD57+, CD68+ and GrB+ cells. Immune cell profile densities were estimated using stereology. We found significantly lower densities of CD3+, CD4+, CD8+ and CD57+ cells (both intra- and peritumoral) in tissue from patients who had relapse. Also densities of intratumoral CD1a+ cells and peritumoral CD20+, CD45RA+ and CD45RO+ cells were significantly lower among patients with relapse. This study demonstrates striking differences in the cellular immune response between patients with and without relapse within 5 years. The results are of potential value in adjuvant immunotherapy and prediction of prognosis.


Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir.
Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the probability of a compound to cause adverse effects is a cytotoxicity assay. Cytotoxicity of a compound is often measured by dose–response curves assuming the administered doses and intracellular exposures are equal at the time of measurement.However, this may not be true for compounds with low membrane permeability or those which are substrates for drug transporters as intracellular concentrations are determined both by passive permeability and active uptake through drug transporters. We show here that three antiviral drugs, adefovir, cidofovir and tenofovir exhibit significantly increased cytotoxicity in HEK293 cells transfected with organic anion transporter (OAT) 1 and 3 compared to a lack of cytotoxicity in HEK293 wildtype cells. A further look at the media and intracellular drug concentrations showed that 24 h after dosing, all three drugs had higher intracellular drug concentrations than that of media in the HEK-OAT1 cells whereas the intracellular drug concentrations in the wildtype cells were much lower than the administered doses. Comparing cytotoxicity IC(50) values of adefovir, cidofovir and tenofovir based on administered doses and measured intracellular concentrations in HEK-OAT1 cells revealed that intracellular drug concentrations have significant impact on calculated IC(50) values. Tenofovir showed much less intrinsic cytotoxicity than adefovir and cidofovir using intracellular concentrations rather than media concentration. Our data suggest that for low permeable drugs or drugs that are substrates for drug transporters, the choice of cellular model is critical for providing an accurate determination of cytotoxicity.


darfix - data analysis for dark-field X-ray microscopy.
A Python package for the analysis of dark-field X-ray microscopy (DFXM) and rocking curve imaging (RCI) data is presented. DFXM is a non-destructive diffraction imaging technique that provides three-dimensional maps of lattice strain and orientation. The darfix package enables fast processing and visualization of these data, providing the user with the essential tools to extract information from the acquired images in a fast and intuitive manner. These data processing and visualization tools can be either imported as library components or accessed through a graphical user interface as an Orange add-on. In the latter case, the different analysis modules can be easily chained to define computational workflows. Operations on larger-than-memory image sets are supported through the implementation of online versions of the data processing algorithms, effectively trading performance for feasibility when the computing resources are limited. The software can automatically extract the relevant instrument angle settings from the input files' metadata. The currently available input file format is EDF and in future releases HDF5 will be incorporated.


Coordinated expression of Jumonji and AHCY under OCT transcription factor control to regulate gene methylation in wood frogs during anoxia.
Wood frogs (Rana sylvatica) can survive extended periods of whole body freezing. Freezing imparts multiple stresses on cells that include anoxia and dehydration, but these can also be experienced as independent stresses. Under anoxia stress, energy metabolism is suppressed, and pro-survival pathways are prioritized to differentially regulate some transcription factors including OCT1 and OCT4. Jumonji C domain proteins (JMJD1A and JMJD2C) are hypoxia responsive demethylases whose expression is accelerated by OCT1 and OCT4 which act to demethylate genes related to the methionine cycle. The responses by these factors to 24 h anoxia exposure and 4 h aerobic recovery was analyzed in liver and skeletal muscle of wood frogs to assess their involvement in metabolic adaptation to oxygen limitation. Immunoblot results showed a decrease in JMJD1A levels under anoxia in liver and muscle, but an increase was observed in JMJD2C demethylase protein in anoxic skeletal muscle. Protein levels of adenosylhomocysteinase (AHCY) and methionine adenosyl transferase (MAT), enzymes of the methionine cycle, also showed an increase in the reoxygenated liver, whereas the levels decreased in muscle. A transcription factor ELISA showed a decrease in DNA binding by OCT1 in the reoxygenated liver and anoxic skeletal muscle, and transcript levels also showed tissue specific gene expression. The present study provides the first analysis of the role of the OCT1 transcription factor, associated proteins, and lysine demethylases in mediating responses to anoxia by wood frog tissues.


Developmental changes in glycolipids and synchronized expression of nutrient transporters in the mouse small intestine.
Small intestinal epithelial cells are rich in characteristic glycosphingolipids (GSLs) that are composed of phytosphingosine and alpha-hydroxy fatty acid, but the physiological roles of GSLs in the small intestine remain unclear. Here, we report the developmental changes in GSL composition in the mouse small intestine (duodenum through ileum) and their relationship with the temporal mRNA expression of nutrient transporters. Up to 2 weeks after birth, the major GSLs were hexosylceramide (HexCer), GM3, GM1 and GD1a. After 2 weeks of age, HexCer and asialo GM1 became the major GSLs. The ceramide moiety of both HexCer and asialo GM1 was composed mainly of phytosphingosine and alpha-hydroxy fatty acid, from birth through adulthood. Immunohistochemically, GM1 localized in the cytoplasm, and asialo GM1 localized exclusively in the apical microvillous membrane of small intestinal epithelial cells. The shift from sialylated GSLs to asialo GM1 was achieved by the combinational and tissue-specific transcriptional down-regulation of GM3 synthase and GM1-beta-galactosidase at around 2 weeks of age. The temporal mRNA expression of various nutrient transporters also showed significant changes at around 2 weeks of age, including the up-regulation of the sodium/glucose cotransporter and the oligopeptide transporter, as well as the down-regulation of amino acid transporters. These synchronized changes in the mRNA expression of nutrient transporters with GSL composition during suckling-to-weanling transition suggest the contributions of GSLs to morphologic and functional development in the membrane of mouse small intestinal epithelial cells.


Development and validation of the Asian version of the oucher: a pain intensity scale for children.
The present study was designed to develop and test the validity of the Asian version of the Oucher pain intensity scale, with color photographs of Taiwanese children as the pain intensity cues. A series of 3 studies were conducted. The aim of the first study was to create male and female versions of the Asian Oucher poster. Each poster consisted of 6 color photographs of children's faces, ranging from "no hurt at all" (scored as 0) to the "biggest hurt you could ever have" (scored as 5). In the second study, 220 children aged 3 to 6 years were recruited to examine the content validity. Children who were able to complete a Piagetian seriation task were asked to choose the sequence of 6 photographs. Photo sequences were adjusted according to the study findings. The third study was conducted to examine the convergent, discriminate, and clinical validity for children who are at different levels of pain intensity. In total, 111 children aged 3 to 10 years old who were experiencing surgical pain were recruited. The construct validity of the Asian Oucher was supported. This study developed an Asian version of Oucher, with photographs of facial expressions of real Taiwanese children who were experiencing pain. The Asian Oucher can assess pain for children as young as 3 years old.


Polyubiquitin binding and cross-reactivity in the USP domain deubiquitinase USP21.
Modification of proteins by ubiquitin (Ub) and Ub-like (Ubl) modifiers regulates a variety of cellular functions. The ability of Ub to form chains of eight structurally and functionally distinct types adds further complexity to the system. Ub-specific proteases (USPs) hydrolyse polyUb chains, and some have been suggested to be cross-reactive with Ubl modifiers, such as neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and interferon-stimulated gene 15 (ISG15). Here, we report that USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8. A crystal structure of USP21 in complex with linear diUb aldehyde shows how USP21 interacts with polyUb through a previously unidentified second Ub- and ISG15-binding surface on the USP domain core. We also rationalize the inability of USP21 to target NEDD8 and identify differences that allow USPs to distinguish between structurally related modifications.


Prevalence of lower extremities peripheral arterial disease among Egyptian ischemic patients attending cardiac rehabilitation unit.
Atherosclerosis is progressive and diffuse pathological disorders which can simultaneously affect multiple vascular beds. Diagnosing Lower extremities peripheral arterial disease (PAD) in patients with Coronary artery disease (CAD) admitted to cardiac rehabilitation program can help to tailor exercise regimen to fit these patients, in addition, early treatment and/or intervention may help to control progression of the disease. The study is to search for the prevalence of undiagnosed PAD using ankle brachial index (ABI) in Egyptian patients with documented CAD undergoing cardiac rehabilitation program. The study included 200 patients with documented CAD scheduled for cardiac rehabilitation in Cardiology department, Ain Shams University, with exclusion of patients with known (diagnosed) PAD. All patients underwent ABI using Doppler ultrasonography. The patients were divided into two groups; Study group with positive ABI (≤ 0.9) and Control group with negative ABI (> 0.9). We found that the prevalence of undiagnosed PAD in those patients was 14.5% (29 patients). The incidence of PAD is increased in patients above 60 years (p = 0.001) and in presence of hypertension/uncontrolled systolic blood pressure (p = 0.002), Dyslipidemia (p = 0.005), or family history of ischemic heart disease (p = 0.035). PAD is associated also with impaired left ventricular systolic function and presence of segmental wall motion abnormalities at rest. Impaired eGFR increased the risk of development of PAD (p = 0.016). PAD was associated more with patients presented by multivessel lesions by coronary angiography and in presence of ischemic ECG changes. This study shows that significant PAD is present in almost 15% of ischemic Egyptian patients. We recommend ABI to be done routinely in patients with significant CAD for exclusion or diagnosis of PAD to help in treatment and improving quality of life in addition to modification of cardiac rehabilitation program in presence of PAD according to its severity.


Protective effects of an anti-4-HNE monoclonal antibody against liver injury and lethality of endotoxemia in mice.
4-hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product that is known to be elevated during oxidative stress. During systemic inflammation and endotoxemia, plasma levels of 4-HNE are elevated in response to lipopolysaccharide (LPS) stimulation. 4-HNE is a highly reactive molecule due to its generation of both Schiff bases and Michael adducts with proteins, which may result in modulation of inflammatory signaling pathways. In this study, we report the production of a 4-HNE adduct-specific monoclonal antibody (mAb) and the effectiveness of the intravenous injection of this mAb (1 mg/kg) in ameliorating LPS (10 mg/kg, i.v.)-induced endotoxemia and liver injury in mice. Endotoxic lethality in control mAb-treated group was suppressed by the administration of anti-4-HNE mAb (75 vs. 27%). After LPS injection, we observed a significant increase in the plasma levels of AST, ALT, IL-6, TNF-α and MCP-1, and elevated expressions of IL-6, IL-10 and TNF-α in the liver. All these elevations were inhibited by anti-4-HNE mAb treatment. As to the underlining mechanism, anti-4-HNE mAb inhibited the elevation of plasma high mobility group box-1 (HMGB1) levels, the translocation and release of HMGB1 in the liver and the formation of 4-HNE adducts themselves, suggesting a functional role of extracellular 4-HNE adducts in hypercytokinemia and liver injury associated with HMGB1 mobilization. In summary, this study reveals a novel therapeutic application of anti-4-HNE mAb for endotoxemia.


Increased dopamine metabolism in the nucleus accumbens and striatum following consumption of a nutritive meal but not a palatable non-nutritive saccharin solution.
This study examined the concentrations of dopamine (DA) and its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of rats that were either 20 hr food deprived or had been given 1 hr of access to food pellets, a liquid diet, or a palatable 0.4% saccharin solution. Significant increases were observed in the HVA/DA ratio in both structures following ingestion of either liquid diet or food pellets. Increases in the DOPAC/DA ratio were observed only after the ingestion of liquid diet. Ingestion of saccharin solution had no effect on any index of DA activity. These results indicate that the type of food ingested can influence dopaminergic responses to feeding, and argue against an exclusive role for motor or reward processes in determining DA activity.


Does activity affect residual limb skin temperatures?
Many lower limb amputees experience thermal discomfort as a result of wearing a prosthesis. The development of new prosthetic technology to address thermal discomfort requires an understanding of how activity (or inactivity) affects residual limb skin temperatures and how skin temperatures are mapped across the skin-prosthesis interface. We studied skin temperatures inside the socket and suspension system of unilateral transtibial amputees to determine the following: (1) Does residual limb skin temperature change as a function of activity and its cessation? (2) If changes occur, are there regional differences (circumferential or proximal-distal) in temperature? Nine unilateral transtibial amputees provided informed consent to participate in this institutional review board-approved study. Residual limb skin temperatures inside their prosthesis were measured at 16 distributed sites using thermistor sensors and a portable data acquisition system. The 150-minute protocol began with a 60-minute seated rest, continued with a 30-minute treadmill walk at a self-selected speed, and concluded after a second 60-minute seated rest. Data from the last minute of each of the three periods were used for analysis. The skin temperature was 31.0° ± 1.5° C (mean ± SD) at the end of the initial rest period. After 30 minutes of treadmill walking, skin temperature increased to 34.1° ± 1.3° C, an increase of 3.1° C (95% confidence interval [CI], 2.4-3.8; p < 0.001). After the final 60 minutes of rest, the skin temperature was 33.2° ± 1.2° C, 0.9° C lower (95% CI, 0.5-1.2; p < 0.001) than at the end of treadmill walking but 2.2° C higher (95% CI, 1.4-2.9; p < 0.001) than the temperature observed at the end of the initial rest period. Skin temperatures were warmest over the tibialis anterior region (p < 0.006) and decreased from the most proximal to the most distal locations on the residual limb (p = 0.001). Walking causes a dramatic increase in skin temperatures inside the prosthesis and subsequent rest of twice the walking duration fails to return temperatures to their initial condition. Rest alone is likely to be insufficient to provide thermal relief without doffing the prosthesis. New prosthetic technology is needed to address this problem. Skin temperatures also varied by residual limb location, suggesting that the development of location-specific technology would be advantageous.


Clinical implications of the invagination of an interwoven nitinol stent: a single-center retrospective analysis.
Stent invagination (SIV) sometimes occurs during interwoven nitinol stent (IWS) placement due to its complex deployment system. It may cause stent malapposition and reduce the minimum stent area. However, the clinical implications of SIV remain unclear. This retrospective single-center study sought to assess the clinical implications of IWS invagination in the femoropopliteal lesions in patients with peripheral arterial diseases. Thirty-two consecutive patients (23 men, mean age of 74 years, 34 limbs) with symptomatic femoropopliteal lesions who had received IWS implantation from January to July 2019 were enrolled. The study was approved by the ethics committee of our institution. The 12-month primary patency rate after the initial IWS placement was evaluated as the primary outcome, which was compared between lesions with SIV (SIV cohort) and without SIV (non-SIV cohort). All IWSs were deployed successfully, but nine cases (26.4%) of SIV occurred during placement. The mean lesion length was 22.3 cm, and critical limb threatening ischemia was observed in 40.6% of the limbs. The overall 12-month primary patency rate was 78.2%. The non-SIV cohort (25 cases) showed a significantly higher primary patency rate than the SIV cohort (9 cases, 91.7% vs. 41.7%, P = 0.0149). IWS implantation showed acceptable durability in Japanese patients in a real-world setting, however, SIV during IWS placement possibly led to a lower 12-month primary patency rate.


Interaction between arteriosclerosis and the APOE4 gene in cognitive decline in older adults: a cross-sectional study in rural minority areas in western China.
Numerous studies have confirmed that the apolipoprotein E4 allele (APOE4) gene and arteriosclerosis (AS) have a combined effect on the occurrence of cognitive function impairment, and dyslipidaemia levels are significantly correlated with APOE4 levels and AS. Few studies have focused on the combined effect of the APOE4 gene and AS on cognitive function. Therefore, this study aimed to investigate the effect of APOE4 gene and AS acting together on cognitive function through dyslipidaemia levels, which could provide certain scientific research value for future studies. A multi-stage cluster sampling method was used to investigate older adults aged 60 years and above in rural areas of Guizhou, China. The demographic sociological characteristics were collected, and laboratory tests, blood lipid measurements, and physical examinations were performed. Mini-Mental State Examination (MMSE) was used to determine cognitive function. Analysis of variance with two-factor factorial design was used to analyse the interaction between the APOE4 gene and AS on cognitive function and its domains. A total of 549 elderly subjects were eligible for this study. The result of the factorial design analysis revealed there was a significant interaction between the APOE4 gene and AS in terms of attention and numeracy (F = 6.878, P = 0.009). The combination of the APOE4 gene and AS leads to a decrease in the level of attention and numeracy domains, and certain attention should be focused on such populations in the future.


Albumin evolution in polyploid species of the genus Xenopus.
Electrophoresis of serum from 21 Xenopus species and subspecies reveals variable numbers of albumin bands. The diploid X. tropicalis has one albumin, while the tetraploid species (laevis, borealis, muelleri, clivii, fraseri, epitropicalis) have two. The octoploid species (amieti, boumbaensis, wittei, vestitus, andrei) have two to three bands, and the dodecaploid X. ruwenzoriensis has three. The molecular weight of the Xenopus albumins varies from 68 kd (in the tropicalis group) to 74 kd. The subspecies of X. laevis possess two albumins of different molecular weights (70 and 74 kd), whereas most species have only 70-kd albumins. Peptide maps have been obtained from albumin electromorphs by limited proteolysis in sodium dodecyl sulfate (SDS) gels, using S. aureus V8 protease. The peptide patterns produced by electromorphs from the same tetraploid Xenopus species generally differ from each other, suggesting that the two albumin genes contain a substantial amount of structural differences. In addition, the peptide maps are diagnostic for most tetraploid species and for some subspecies of X. laevis as well. Proteolysis of albumins from most octoploid and dodecaploid species results in patterns which are very similar to the ones produced by the electromorphs from X. fraseri. The albumins of X. vestitus differ from those of the other octoploid species. X. andrei possesses two fraseri-type and one vestitus-type albumin, which indicates that it probably originated by allopolyploidy.


The effect of combination therapy of allicin and fenofibrate on high fat diet-induced vascular endothelium dysfunction and liver damage in rats.
It is designed to investigate the effects of combination therapy of allicin and fenofibrate on the endothelial and liver functions in rats with hyperlipidemia. The healthy male Wistar rats fed high fat diet were treated with fenofibrate (80 mg/kg per day) alone, allicin (60 mg/kg per day) alone and a lower dosage of combined therapy (allicin 20 mg/kg per day and fenofibrate 30 mg/kg per day) respectively for 8 weeks. The serum levels of cholesterol, triglyceride, nitrogen oxidative, alanine transferase (ALT) and aspartate transferase (AST) were determined. Acetylcholine-induced endothelium-dependent vascular relaxation (EDVR) of aorta rings was tested, and the morphologic changes of liver tissue were observed. Compared with high fat diet control, fenofibrate alone or the combined therapy increased remarkably the levels of high density lipoprotein respectively (P<0.05). Both single and combined therapy of fenofibrate and allicin significantly enhanced the levels of NO (P<0.01 or P<0.05), but the combined therapy had greatest high EDVR responses (P<0.01). Furthermore, the reduced levels of ALT and AST were significantly obvious in the combined therapy groups (P<0.01 or P<0.05). In addition, the lower dosage of combined therapy significantly ameliorated severe fatty degeneration of liver cells occurred in the high fat diet fed rat although the single fenofibrate treatment showed spotty necrosis of liver cells and bile duct expansion. Combination therapy with allicin and fenofibrate can effectively enhance the protective effects on endothelial function and reduce the hepatic damage in rats with hyperlipidemia.


Induction of Sp1-p53 DNA-binding heterocomplexes during granulocyte/macrophage colony-stimulating factor-dependent proliferation in human erythroleukemia cell line TF-1.
The involvement of Sp1 in regulating cell proliferation in myeloid leukemia cells was determined by measuring the levels and DNA binding activity of Sp1 in TF-1 cells, a human erythroleukemia cell line dependent on granulocyte/macrophage colony-stimulating factor (GM-CSF) for viability and cell growth. DNA binding of Sp1 to a specific double-stranded oligodeoxynucleotide was increased markedly in a dose-dependent manner in proliferating cells in response to GM-CSF compared with growth-arrested or apoptotic cells. Competition experiments and mobility shift interference assays with antibodies against Sp1 as well as wild-type or mutant p53 indicated that GM-CSF-inducible DNA-binding complexes contained both Sp1 and p53 and that these heterocomplexes bound to both p53- and Sp1-binding sequences with high affinity. Immunoprecipitation of nuclear extracts with a p53 antibody indicated that Sp1 was associated as a heterocomplex with p53. Formation of this complex was dependent on the level of p53 since p53 was more abundant in proliferating cells and decreased upon induction of growth arrest and apoptosis by withdrawal of GM-CSF while Sp1 levels remained unchanged. These results suggest that the association of Sp1 with p53 may represent a novel mechanism of growth regulation in cytokine-dependent leukemia cells.


Pressure-dependence Raman spectroscopy and the lattice dynamic calculations of Bi2(MoO4)3 crystal.
This work reports a pressure-dependent Raman spectroscopic study and the theoretical lattice dynamics calculations of a Bi2(MoO4)3 crystal. The lattice dynamics calculations were performed, based on a rigid ion model, to understand the vibrational properties of the Bi2(MoO4)3 system and to assign the experimental Raman modes under ambient conditions. The calculated vibrational properties were helpful to support pressure-dependent Raman results, including eventual structural changes induced by pressure changes. Raman spectra were measured in the spectral region between 20 and 1000 cm-1 and the evolution of the pressures values was recorded in the range of 0.1-14.7 GPa. Pressure-dependent Raman spectra showed changes observed at 2.6, 4.9 and 9.2 GPa, these changes being associated with structural phase transformations. Finally, principal component analysis (PCA) and hierarchical cluster analysis (HCA) were performed to infer the critical pressure of phase transformations undergone by the Bi2(MoO4)3 crystal.


A bitter aftertaste: unintended effects of artificial sweeteners on the gut microbiome.
Intestinal microbial communities regulate a range of host physiological functions, from energy harvest and glucose homeostasis to immune development and regulation. Suez et al. (2014) recently demonstrated that artificial sweeteners alter gut microbial communities, leading to glucose intolerance in both mice and humans.


No Healthcare Utilization and Death.
An inappropriately low frequency of healthcare utilization has been reported to be associated with poor control of chronic diseases, accelerating healthcare disparities. However, the evidence is limited regarding the association between no healthcare utilization and mortality. To examine whether individuals without healthcare utilization have the increased risks of mortality among the US general population. Prospective cohort study PARTICIPANTS: Adults aged ≥ 20 years (n = 39,067) in the National Health and Nutrition Examination Survey (NHANES)1999-2014 linked to national mortality data through December 2015. The exposure was the number of visits to healthcare providers during the past year (healthcare utilization): none, 1-3 times (referent), 4-9 times, or ≥ 10 times. Cox hazard regression models were employed to estimate the adjusted hazard ratios (aHR) of all-cause, cardiovascular, and cancer mortality adjusting for socio-demographic characteristics and comorbidities. During a median follow-up of 7.4 years, participants without visit over the past year showed higher risks of all-cause mortality (aHR [95% CI] = 1.16 [1.04-1.30]) and cardiovascular mortality (aHR [95% CI] = 1.62 [1.28-2.05]) than those who visited the office 1-3 times. We found no evidence of the association between no visit and cancer mortality. The association between no providers' office visit and all-cause mortality was stronger among males (aHR [95% CI] = 1.22 [1.06-1.40]) than females (aHR [95% CI] = 0.97 [0.79-1.19]; p-for-interaction = 0.01) and among uninsured individuals (aHR [95% CI] = 1.22 [0.98-1.51]) than insured individuals (aHR [95% CI] = 1.09 [0.95-1.25]; p-for-interaction = 0.04). No providers' office visit over a year was associated with increased risks of all-cause and cardiovascular mortality. Further investigations are warranted to identify the underlying reasons for the elevated mortality risks due to no healthcare utilization.


Skin benefits of moisturising body wash formulas for children with atopic dermatitis: A randomised controlled clinical study in China.
It acknowledged that skin care is an important part of atopic dermatitis therapy. However, clinical evidences are limited for the best bathing practices, especially the skin health performance of cleansing products on children's atopic dermatitis skin. A randomised controlled clinical study was conducted in China among 4- to 18-year-old children with mild-to-moderate atopic dermatitis to evaluate the skin health effect of three cleansing systems (a mild synthetic bar, an ultra-mild body wash with lipids, and an ultra-mild body wash with lipids and zinc pyrithione) by measuring SCORing of Atopic Dermatitis (SCORAD), consumption of topical corticosteroid and the characteristics of microbiome. Increased Staphylococcus aureus abundance and decreased microbial diversity were observed in atopic dermatitis lesion sites compared with healthy control sites. After 4 weeks of treatment, all three treatments showed clinically important improvement from baseline in SCORAD. Four-week corticosteroid consumption was significantly lower for the two body wash groups than the bar group. A significant decrease in S. aureus abundance and increase in microbial diversity were observed in the lesion sites for the two body wash formulas, while the microbial diversity was statistically insignificant for the mild cleansing bar group. However, there were no incremental benefits provided by the body wash formulas based on the assessment of SCORAD. These results demonstrated the safety and efficacy of using the investigational body wash formulas with lipids in reducing the needs for corticosteroid and improving the healthy composition of skin microbiome vs. the mild synthetic bar soap.


Effect of coffee consumption on intraocular pressure.
Many ophthalmologists instruct patients with glaucoma to avoid coffee, although data supporting this practice are insufficient. To estimate the effect of drinking coffee on intraocular pressure (IOP). In this crossover study, the effect of the consumption of regular (180 mg caffeine in 200 mL beverage) and decaffeinated coffee (3.6 mg caffeine in 200 mL beverage) was compared in patients with normotensive glaucoma (n = 6) or ocular hypertension (n = 22). IOP was monitored in both groups at 30, 60, and 90 minutes after coffee ingestion. In patients with normotensive glaucoma who drank regular coffee, the mean +/- SD changes in IOP at 30, 60, and 90 minutes were 0.9 +/- 0.5, 3.6 +/- 1.1, and 2.3 +/- 0.66 mm Hg, respectively; in those who drank decaffeinated coffee, they were 0.75 +/- 0.36, 0.70 +/- 0.4, and 0.4 +/- 0.6 mm Hg, respectively. The corresponding values in patients with ocular hypertension were as follows: after regular coffee, 1.1 +/- 0.7, 3.4 +/- 1.0, and 3.0 +/- 2.7 mm Hg; and after decaffeinated coffee, 0.6 +/- 0.4, 0.9 +/- 0.2, and 0.5 +/- 0.5 mm Hg. The difference in the change in IOP from baseline after ingestion of regular versus decaffeinated coffee was statistically significant in each group at 60 and 90 minutes. Subjects who drank regular coffee demonstrated a greater elevation in IOP; this elevation may be clinically significant. Intake of caffeinated beverage (>/=180 mg caffeine) may not be recommended for patients with normotensive glaucoma or ocular hypertension.


IL-6, IL-10 and IL-17 gene polymorphisms in Iranian women with recurrent miscarriage.
Pro-inflammatory and anti-inflammatory cytokines and polymorphisms of their genes have been described to be involved in the pathogenesis of recurrent miscarriage (RM). To investigate the association between RM and five polymorphisms of cytokine genes, interleukin 10 (IL-10), (-592 A/C, -819 C/T, -1082 A/G), IL-6 (-174 C/G) and IL-17 (-197 G/A) in Iranian women. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to determine the frequencies of the IL-6, IL-10 and IL-17 gene polymorphisms in 85 women with RM compared with 104 healthy controls. The frequencies of IL-10 promoter gene polymorphisms (-592 A/C and -819 C/T) were significantly higher in RM women than those in controls (p=0.003). However, no statistically significant differences were observed in the frequencies of IL-6 (-174 C/G), IL-10 (-1082 A/G) and IL-17 (-197 G/A) polymorphisms between RM women and controls. These results suggest that IL-10 gene polymorphism screening might have some relevance in patients with RM, a suggestion which requires further studies.


Synchronized nonpharmaceutical interventions for the control of COVID-19.
The world is experiencing an ongoing pandemic of coronavirus disease-2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In attempts to control the pandemic, a range of nonpharmaceutical interventions (NPIs) has been implemented worldwide. However, the effect of synchronized NPIs for the control of COVID-19 at temporal and spatial scales has not been well studied. Therefore, a meta-population model that incorporates essential nonlinear processes was constructed to uncover the transmission characteristics of SARS-CoV-2 and then assess the effectiveness of synchronized NPIs on COVID-19 dynamics in China. Regional synchronization of NPIs was observed in China, and it was found that a combination of synchronized NPIs (the travel restrictions, the social distancing and the infection isolation) prevented 93.7% of SARS-CoV-2 infections. The use of synchronized NPIs at the time of the Wuhan lockdown may have prevented as much as 38% of SARS-CoV-2 infections, compared with the unsynchronized scenario. The interconnectivity of the epicenter, the implementation time of synchronized NPIs, and the number of regions considered all affected the performance of synchronized NPIs. The results highlight the importance of using synchronized NPIs in high-risk regions for the control of COVID-19 and shed light on effective strategies for future pandemic responses. The online version contains supplementary material available at 10.1007/s11071-021-06505-0.


Identification and nucleotide sequence of the activator gene of the externally induced phosphoglycerate transport system of Salmonella typhimurium.
A recent study from this laboratory (G-q. Yu, D. Goldrick, H.R. Kaback and J-s. Hong, in preparation) indicates that the externally induced phosphoglycerate transport system (pgt) of Salmonella typhimurium is positively regulated by the activator gene, pgtA, and that the pgtA is localized in the SalI-PstI restriction fragment 3.0 kb from the permease gene, pgtP. In this paper, we describe the identification of the activator gene and its gene product and the determination of the complete nucleotide (nt) sequence of the activator gene as well as of a downstream gene not required for pgtP expression. The amino acid sequence of the activator based on the nt sequence shows an N-terminal signal-like sequence which is apparently not cleaved and three potential transmembrane sequences in the C-terminal half of the protein based on the hydropathy analysis.


Statin-induced autoimmune necrotizing myositis-A single-center case series highlighting this potentially life-threatening but treatable condition.
Statin-induced autoimmune necrotizing myositis is a rare but important cause muscle weakness. Withdrawal of the statin and steroid treatment alone may be insufficient treatment for SIANM. Targeted immunosuppression may be needed and can be effective.


Distant metastases from head and neck squamous cell carcinoma. Part II. Diagnosis.
The detection of distant metastases is critical for prognostication and for the choice of treatment in patients with head and neck squamous cell carcinoma (HNSCC). Pretreatment screening for distant metastases should be conducted particularly for patients with high risk factors, prior to locoregional treatment decisions. Different diagnostic techniques are discussed. Unfortunately, most studies lack sufficient follow-up to reliably assess false-negative results. Moreover, the designs of most studies vary substantially with regard to homogeneity of groups (tumor types and stages), timing (pretreatment, follow-up) and definition of risk factors (patient selection). Therefore, only a few studies are comparable. The combination of F-18 fluoro-d-glucose-positron emission tomography (FDG-PET) and a dedicated CT (at least of the chest) is the most important imaging protocol at the present time. Eventually, whole-body-MRI (WB-MRI) may possibly replace PET-CT for screening patients for distant metastases.


Validation and deployment of a quantitative trapping method to measure volatile antimony emissions.
Microbial-mediated Sb volatilization is a poorly understood part of the Sb biogeochemical cycle. This is mostly due to a lack of laboratory and field-deployable methods that are capable of quantifying low-level emissions of Sb from diffuse sources. In this study, we validated two methods using a H2O2 -HNO3 liquid chemotrap and an activated coconut shell charcoal solid-phase trap, achieving an absolute limit of detection of 4.6 ng and below 2.0 ng Sb, respectively. The activated charcoal solid-phase trapping method, the most easily operated method, was then applied to contaminated shooting range soils. Four treatments were tested: 1) flooded, 2) manure amended + flooded, 3) 70 % water holding capacity, and 4) manure amendment +70 % water holding capacity, since agricultural practices and flooding events may contribute to Sb volatilization. Volatile Sb was only produced from flooded microcosms and manure amendment greatly influenced the onset and amount of volatile Sb produced. The highest amount of volatile Sb produced, up to 62.1 ng kg-1 d-1, was from the flooded manure amended soil. This suggests that anaerobic microorganisms may potentially be drivers of Sb volatilization. Our results show that polluted shooting range soils are a source of volatile Sb under flooded conditions, which may lead to an increase in the mobility of Sb. Some of these volatile Sb species are toxic and genotoxic, highlighting the role of Sb volatilization on environmental health, especially for individuals living in contaminated areas exposed to wetlands or flooded conditions (e.g., rice paddy agriculture surrounding mining areas). This work paves way for research on Sb volatilization in the environment.


Short latency trigemino-sternocleidomastoid response in patients with migraine.
To investigate the central trigeminal circuits in migraine patients. Short latency responses can be recorded in sternocleidomastoid (SCM) muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex was investigated in 20 healthy subjects, in 20 patients suffering from migraine with aura (MWA) and in 20 patients suffering from migraine without aura (MWOA) during and between the attacks. The trigemino-cervical responses were bilaterally abnormal in 17 patients with MWA and 15 patients with MWOA during the headache attacks, in 11 patients with MWA and in 10 patients with MWOA during the interictal period. In the patients with normal trigemino-cervical responses during the pain-free phase the triptan was significantly more effective at relieving headache. Our findings further support and emphasise the role of the trigeminal system in the pathogenesis of migraine. The bilateral location of the abnormalities suggests a centrally located dysfunction. Therefore, the trigemino-cervical reflex is sensitive in disclosing a disturbed brainstem activity and may be an index of neuronal activity in the human brainstem; moreover their assessment may help as valuable prognostic tool for predicting the efficacy of triptans therapy.


Structure-activity relationships of aromatic retinoids on the differentiation of the human histiocytic lymphoma cell line U-937.
The differentiation-inducer activity of a series of derivatives modified on the terminal ring, the polyene side-chain or the polar end group of the retinoic acid molecule was tested on the human histiocytic lymphoma cell line U-937 and compared with that of all-trans-retinoic acid. Only retinoids with both an unsaturated terminal end ring and a free carboxyl polar end group were found to be active in this system. Introduction of an aromatic ring in place of the first double bond of the side chain increased highly the activity whereas cyclisation of the last two double bonds decreased it. Replacement of the unsaturated terminal ring by an aromatic ring abolished the activity as did the esterification of the carboxyl end group or its replacement by a sodium sulfinate, sodium sulfonate or ethyl sulfone end group. All but only the active retinoids induced the same morphological and biochemical changes on U-937 cells, suggesting that they have the same route of action. However, biologically inactive retinoids were shown to be able to inhibit the differentiation of U-937 cells, induced by active ones, indicating that they can compete for a common "receptor".


Arylsulfatase A pseudodeficiency in Chinese.
Arylsulfatase A (ASA) pseudodeficiency was found to be much rarer in Taiwan than in most western countries (2.5% versus 7.3%-20% carrier rate). The linkage of two mutations (A2725G and A1788G) in the pseudodeficiency allele was preserved in Chinese, and A2725G did not occur alone. This unusual linkage of mutations has not been fully explained previously because the frequency of A2725G alone was not clear (as low as 4% in the only report). However, A1788G was found in 55 of 160 (34.4%) DNA samples tested in this study. These data suggest that the A2725G mutation occurred in DNA that already contained the A1788G change, at an ancient time in one of our common ancestors.


An Alternative to Mother's Own Milk: Maternal Awareness of Donor Human Milk and Milk Banks.
The use of donor human milk is rising. Maternal awareness of donor human milk use, milk donation, and milk banks has not been well described in the United States. To explore maternal experience, knowledge, and attitudes regarding donor human milk use and milk donation. We also assessed counseling by medical providers about donor human milk use and donation. A cross-sectional prospective survey design was used in this study. We anonymously surveyed mothers (N = 73) attending the 1 to 2-week well newborn appointment. Analyses were completed using one-way ANOVA and logistic regression. Participants' infants primarily received their own mother's milk (87%, n = 61). No infants received donor human milk, but 4% (n = 3) of participants donated milk. The majority of participants had positive responses to attitudinal statements about donor milk. When presented with a hypothetical scenario, participants chose formula (89%, n = 59) over donor human milk (11%, n = 7) for their infant. Moreover, if donor human milk was the only option available, they chose donor human milk from a relative or friend (60%, n = 40) over a milk bank (40%, n = 26). Medical providers had discussed donor human milk use or donation with 4% (n = 3) of participants. The majority of participants previously had minimal experience using donor human milk and limited knowledge regarding donor human milk and milk banks. According to participants, medical providers did not routinely discuss milk donation and the role of donor human milk with families.


Functional organization of auditory cortical fields in the Mongolian gerbil (Meriones unguiculatus): binaural 2-deoxyglucose patterns.
Unilaterally deafened (cochlear destruction) gerbils were exposed to white noise after injection of 14-C-2-deoxyglucose. The labelling patterns were compared to those of unstimulated operated animals, noise stimulated control animals and bilaterally ear plugged animals. Serial transverse, horizontal and tangential autoradiographs through the cortex were analysed. In lesioned animals, labelling was strongly reduced on the side contralateral to the lesion in the high frequency regions of A1 and the anterior auditory field (AAF). We assume that these regions correspond to the high frequency EI cell areas. Fine banding could be seen superimposed on this pattern in transverse and tangential sections. We suggest that this may be due to alternating strips of EI and EE cells orthogonal to iso-frequency contours. In the low frequency regions of A1 and AAF, labelling asymmetries were also present, but were less pronounced. We assume that these effects are due to low frequency EE cells. In sub-cortical structures, labelling was reduced in the inferior colliculus and ventral part of the medial geniculate body contralateral to the lesioned ear, but no labelling pattern was visible. We presume that the spatial separation of EE and EI inputs to these structures is not marked enough to allow labelling patterns to be seen. In the superior olivary complex, labelling was reduced on the side contralateral to the lesioned ear in the medial dendritic field of the medial superior olivary nucleus and in the nucleus of the trapezoid body. Ipsilateral to the lesioned ear, labelling was reduced in the lateral dendritic field of the medial superior olive.


Safety, efficacy, and tolerability of nelfinavir-containing antiretroviral therapy for patients coinfected with HIV and hepatitis C undergoing methadone maintenance.
The safety, efficacy, and tolerability of nelfinavir (NFV)-containing antiretroviral therapy were evaluated in patients coinfected with HIV and hepatitis C undergoing methadone maintenance at an urban outpatient opioid treatment program serving a minority adult population. Eligibility covered methadone-maintained patients coinfected with HIV and hepatitis C who had received or were currently receiving NFV. The yield was 51 case patients. Parameters examined looked into safety, efficacy, and tolerability. Nelfinavir was discontinued in 2 patients for liver function abnormalities but resumed in 1 patient. One patient developed laboratory abnormalities during NFV therapy that were not present before NFV therapy; in 12 case patients, pre-NFV therapy liver function abnormalities resolved completely during NFV therapy. There was a statistically significant increase in CD4 count during NFV therapy. Viral load decreased or was unchanged in 10 case patients and increased in 8, of whom 5 had a CD4 count increase during NFV therapy. Three patients had diarrhea and 4 patients had constipation. Nelfinavir was not discontinued -- neither was dose adjusted -- in any of these patients. Patients who had received NFV > or =36 months had a smaller increase in mean methadone dose as compared with patients who had received NFV <36 months. The results show that NFV is safe, efficacious, and well tolerated.


Quantification of zidovudine and its monophosphate in cell extracts by on-line solid-phase extraction coupled to liquid chromatography.
A simple and rapid analytical method for the simultaneous quantification of zidovudine (AZT) and its monophosphate (AZTMP) in cell extracts has been developed using high-performance liquid chromatography (HPLC) with on-line solid-phase extraction and 2-aminoethyl-3'-azido-2',3'-dideoxythymidin-5'-yl phosphodiester sodium salt as internal standard (IS). The cell extract samples were directly injected on a short reversed-phase precolumn using an aqueous buffer containing an ion-pairing reagent as a mobile phase. Under these conditions, the analytes were retained on the precolumn whereas the proteins were discarded. The analytes were then transferred onto the analytical column by increasing the strength of the eluent. The calibration curve was linear over a concentration range of 0.5-100 microg/ml. Inter- and intra-day accuracy and precision results satisfied the accepted criteria for bioanalytical validation. This method was used to study the decomposition pathway of a model pronucleotide in an in vitro approach.


Pentobarbital and synaptic high-affinity receptive sites for gamma-aminobutyric acid.
Electrophysiological investigations of others show that pentobarbital enhances the inhibitory inflences of gamma-aminobutyric acid (GABA). Specifically, receptor activation is amplified and prolonged, suggesting the presence of an increased number of GABA molecules in the synaptic cleft. Either inactivation of high-affinity GABA transport or alteration of post-synaptic GABA receptors might account for these influences of pentobarbital. In this sudy the effect of pentobarbital on high-affinity uptake and binding of GABA to synaptic receptive sites has been examined. Using synaptosomes and subsynaptosomal fractions of cerebral cortex and hippocampus, it si shown that concentrations of pentobarbital, exceeding 1 mM have no appreciable effect on GABA uptake or binding. Thus the synaptic influence of pentobarbital, evident at 0.1 mM in electrophysiologic experiments, must originate from mechanisms other than the high-affinity uptake or binding of GABA. Possible sites of action include the presynaptic release of GABA and the ionophores coupled with postsynapitc sites.


Caring for patients with co-occurring mental health & substance use disorders.
Consider substance abuse if Tx for mood or anxiety disorders is ineffective. Don't defer treating a mental health issue until a substance use disorder is resolved.


Born out of wedlock and never married--it breaks a man's heart.
This study examines whether men who were born outside marriage in early twentieth century Sweden run a higher risk of dying from ischaemic heart disease (IHD) in middle and old age compared to men who were born inside marriage. Analyses are based on the male half of the Uppsala Birth Cohort Study, Sweden, consisting of all 7411 boys who were born alive at the Uppsala Academic Hospital during the period 1915-1929. The statistical method used is Cox regression. The results demonstrated a statistically significant excess mortality among men born outside marriage, which could not be explained by either social class of origin or birth weight for gestational age. Instead, this elevated mortality was largely explained by the more than doubled mortality risk among those men born outside wedlock who never married in relation to the corresponding group of men born to married parents. Even when three indicators of adult socio-economic status were adjusted for, men who never married and were born outside marriage still ran a 93 per cent higher risk of dying from IHD than men who never married but were born inside marriage. This intervening effect of adult marital status was restricted to the category of never married men. Thus, although divorcees demonstrated an even higher mortality risk in relation to the married than did those who never married, this was equally true for men born inside and men born outside marriage. In the concluding section of the paper I argue that these findings should be understood in terms of the childhood social stigma that the illegitimate children experienced. This stigma may have resulted in an increased susceptibility, which in combination with the "failure" in adulthood to comply with the established norms of society regarding matrimony led to higher levels of IHD mortality in middle and old age.


[Clinical and morphological findings in Tangier disease (hypo-alpha-lipoporteinaemia) and its ENT-significance (author's transl)].
The report deals with the first three cases of Tangier disease (Hypo-alpha-Lipoproteinaemia) observed in Germany. This rare metabolic disorder is distinguished by a diminution of HDL-Lipoproteins in serum and a lipid storage in histiocytes. The prominent symptom is the orange yellow discolouration of hyperplastic tonsills and adenoids; further symptoms of the disease generally are various, the development is little typical. The morphological substrat of the deranged fat metabolism is cholesteryl ester storage in the reticuloendothelial system, smooth muscle cells, pericytes and Schwann cells of peripheral nerves. M. Tangier can be differentiated from other lysosomal defects by ultrastructural and chemical parameters, it seems to have a autosomal recessive inheritance. It is the ENT-specialist, who can establish an early diagnosis of this disease, provided he is aware of its clinical features.


Radioimmunoassay of plasma digoxin in nephrotic syndrome.
Plasma digoxin was determined by three different radioimmunoassays in blood samples from 12 patients with hypoalbuminemia before and after increasing the concentration of albumin and TBG. With the Clinical-Assays-[125I]-Kit and the Schwarz/Mann-[3H]-Kit reliable digoxin values were obtained even in patients with severe nephrotic syndrome.


Behavior of 4 types of paper with printed QR codes for evaluating denture marking in conditions of extreme heat.
Quick response (QR) codes are a fast and efficient technology for linking and accessing identifying information, and their use has been proposed in forensics. The heat resistance and esthetics of denture marking methods (DMMs) have been recommended by the American Dental Association (ADA), but studies on these aspects of printed QR codes are lacking. The purpose of this study was to determine the optimal printed material with QR codes for implementation as a DMM adjusted to the recommendations of the ADA. The behavior of 4 types of paper, bond paper, fiberglass filter paper, ultralong hydroxyapatite nanowire paper, and polyolefin and silica paper with printed QR codes was analyzed. They were exposed to temperatures between 100 °C and 1000 °C in a heat muffle for 1 hour. Each specimen was subjected to both a morphological and a thermogravimetric analysis (TGA) and scanned by using 3 different smartphones. The scans were positive for bond paper (33.3%), fiberglass fiber paper (50%), ultralong hydroxyapatite nanowire paper (100%), and polyolefin and silica paper (70.4%). The TGA revealed continuous decomposition curves (average 16.5 minutes at 624 °C). Printed QR codes on ultralong hydroxyapatite nanowire paper appear to be suitable as information reservoirs, even surviving incineration, and may be implemented as a DMM conforming to the ADA recommendations.


Endovascular treatment of aortic coarctation with a novel BeGraft aortic stent in children and young adults: a single-centre experience with short-term follow-up results.
We present our experience and outcomes with the BeGraft in the treatment of aortic coarctation in a predominantly paediatric population. This study includes a retrospective analysis of patients who had Begraft aortic stent implantation between 2018 and 2020 from a single centre. The BeGraft aortic stent was used in 11 patients (7 males, 4 females) with a median age of 14 (13-21) years and a median weight of 65 (46-103) kg. Coarctation was native in five patients and recurrent in six patients. Median stent diameter and length were 16 mm and 38 mm, respectively. The median peak-to-peak pressure was 30 (12-55) mmHg before the procedure and 5 (0-17) mmHg after the procedure. The stenting procedure was successful in 10 of the 11 patients. Stent migration to the abdominal aorta occurred on post-procedure day 1 in the 21-year-old patient, who had previously undergone surgical closure of the ventricular septal defect and balloon angioplasty for coarctation. After repositioning failed, the stent was safely fixed in the abdominal aorta. Strut distortion also occurred during balloon retrieval in one patient, but no aneurysm or in-stent restenosis was observed at 1-year follow-up. The patients were followed for a median of 14 (4-25) months and none required redilation. Our initial results demonstrated that the BeGraft aortic stent effectively reduced the pressure gradient in selected native and recurrent cases. Despite advantages such as a smaller sheath and low profile, more experience and medium- to long-term results are needed.


In vitro effect of toothpaste with low fluoride combined with sodium trimetaphosphate on dentine erosion.
This study sought to evaluate in vitro the effect of a dentifrice containing sodium trimetaphosphate (TMP) combined or not with low fluoride (500 ppm NaF) on dentine erosion of intrinsic origin. Human root dentine blocks were selected based on surface microhardness and randomly allocated into five groups (n = 12): negative control (0 ppm F; no TMP); F500 (500 ppm NaF); F1500 (1500 ppm NaF-positive control); TMP (1% TMP); and F + TMP (500 ppm NaF + 1% TMP). The blocks were submitted to erosion cycles (3 ×/day) for 3 days (0.01 M HCl, pH 1.5-30 s), treatment (1 min-1:3 p/p dentifrice/distilled water) and remineralization (artificial saliva/120 min). Dentine alterations were determined according to the percentage of microhardness loss (%HL), surface loss (SL) and surface analysis by scanning electron microscopy. The data were analyzed using one-way ANOVA (p < 0.05). The values of SL and %HL in each group were, respectively: negative control (1.36 ± 0.36; 57.29 ± 14.14), F500 (1.46 ± 0.28; 65.66 ± 5.11), F1500 (1.52 ± 0.36; 61.66 ± 5.15), TMP (1.45 ± 0.45; 62.08 ± 3.83) and F + TMP (1.38 ± 0.42; 63.38 ± 6.47). There was no statistically significant difference in all the parameters (p = 0.873 and p = 0.152). The dentifrices containing TMP combined or not with fluoride were not able to prevent dentine erosion.


Predictors of Clinical Outcomes in Autologous Cranioplasty.
Cranioplasty is a common neurosurgical procedure and autologous grafts are preferred due to their aesthetic and biocompatibility benefits. Multiple risk factors are implicated as predictors for neurologic outcome. This study focuses on risk factors that may be associated with complications and analyzes the predictors of neurologic outcomes after autologous cranioplasty. This is a retrospective observational study conducted at a tertiary care center between 2015 and 2021. Adults with autologous cranioplasty (n = 132) were recruited from procedure logs and the hospital electronic health record. Clinicodemographic parameters, risk factors, and complications were recorded. Neurologic outcomes were measured using the dichotomized Glasgow Outcome Scale (GOS). Primary outcome measure was pre- and post-cranioplasty GOS at the last follow up. Secondary outcome measures were the predicting factors that contributed to enhanced neurologic outcome post-cranioplasty. Mean age was 41.4 (standard deviation ± 13.5) years with male predominance (12.2:1). Complications developed in 12.9% (n = 17), with infections in 3.8% (n = 5) and hydrocephalus in 2.3% (n = 3). In bivariate analysis, pre-cranioplasty GOS good grades 4 and 5 (P < 0.001), trauma as an indication for decompressive craniectomy (DC) (P < 0.001), and early cranioplasty ≤12 weeks (P = 0.023) were statistically significant predictors for post-cranioplasty neurologic recovery at follow-up. In a multiple logistic regression model, adjusted odds ratio for pre-cranioplasty GOS was 28.77 (95% confidence interval [CI] 7.21-114.74, P < 0.001), for trauma as indication for DC was 5.15 (95% CI 1.65-16.05, P = 0.003), and for early cranioplasty ≤12 weeks was 3.04 (95% CI 1.12-8.27 P = 0.029). Autologous cranioplasty contributes to a quantifiable neurologic outcome. Pre-cranioplasty neurologic status, cranioplasty done for traumatic DC and early cranioplasty may have potential for enhanced neurologic recovery. Further clinical studies with better evidence may expound upon these findings.


Expression of the long noncoding RNA RP11-169D4.1-001 in Hypopharyngeal Squamous cell carcinoma tissue and its clinical significance.
Increased research efforts have demonstrated that lncRNAs are associated with multiple head and neck tumors and play important roles in cancer. We previously found that RP11-169D4.1-001 plays a tumor-suppressive role in laryngeal cancer, but its function in human hypopharyngeal squamous cell carcinoma (HSCC) remains unknown. Thus, this research aimed to analyze the relationship between RP11-169D4.1-001 expression and HSCC clinicopathological features. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the expression of RP11-169D4.1-001 in 70 pairs of HSCC and adjacent normal tissues. The expression level of RP11-169D4.1-001 in HSCC tissues was significantly lower than that in adjacent normal tissues (P = .001). The expression of RP11-169D4.1-001 had no significant relationship with tumor differentiation, stage, smoking, drinking, age, tumor location, or treatment. RP11-169D4.1-001 expression was associated with T category (P = .008) and lymph node metastasis (P = .001). Survival data were assessed by Kaplan-Meier curves. Patients with high RP11-169D4.1-001 expression were found to have a shorter overall survival than patients with low RP11-169D4.1-001 expression. Multivariate analysis also indicated that target RNA was an independent factor for prognosis. The ROC curve was constructed to clarify the diagnostic value of RP11-169D4.1-001. RP11-169D4.1-001 may serve as a new biomarker and potential drug target and can be used as a new biomarker and a potential drug target for the detection and treatment of hypopharyngeal cancer, respectively. Furthermore, RP11-169D4.1-001 expression may be an independent prognostic factor affecting the survival of hypopharyngeal cancer patients.


Cancer chemopreventive effects of a Brazilian folk medicine, Juca, on in vivo two-stage skin carcinogenesis.
Gallic acid (1) and methyl gallate (2) were isolated from Juca, a Brazilian folk medicine, fruits of Caesalpinia ferrea MART (Leguminosae), decreased significantly the average number of papillomas per mouse in the experiment of the promoting effects of 12-O-tetra- decanoylphorbol-13-acetate (TPA) on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA).


Bremsstrahlung parameters of praseodymium-142 in different human tissues: a dosimetric perspective for (142)Pr radionuclide therapy.
Praseodymium-142 [T 1/2 = 19.12 h, [Formula: see text] = 2.162 MeV (96.3%), Eγ = 1575 keV (3.7%)] is one of the (141)Pr radioisotopes. Many studies have been attempted to assess the significance of usage (142)Pr in radionuclide therapy. In many studies, the dosimetric parameters of (142)Pr sources were calculated by modeling (142)Pr sources in the water phantom and scoring the energy deposited around it. However, the medical dosimetry calculations in water phantom consider Bremsstrahlung production, raising the question: "How important is to simulate human tissues instead of using water phantom?" This study answers these questions by estimation of (142)Pr Bremsstrahlung parameters. The Bremsstrahlung parameters of (142)Pr as therapeutic beta nuclides in different human tissues (adipose, blood, brain, breast, cell nucleus, eye lens, gastrointestinal tract, heart, kidney, liver, lung deflated, lymph, muscle, ovary, pancreas, cartilage, red marrow, spongiosa, yellow marrow, skin, spleen, testis, thyroid and different skeleton bones) were calculated by extending the national council for radiation protection model. The specific Bremsstrahlung constant (Γ Br), probability of energy loss by beta during Bremsstrahlung emission (P Br) and Bremsstrahlung activity (A release)Br were estimated. It should be mentioned that Monte Carlo simulation was used for estimation of (142)Pr Bremsstrahlung activity based on the element compositions of different human tissues and the calculated exposures from the anthropomorphic phantoms. Γ Br for yellow marrow was smallest amount (1.1962 × 10(-3) C/kg-cm(2)/MBq-h) compared to the other tissues and highest for cortical bone (2.4764 × 10(-3) C/kg-cm(2)/MBq-h), and, overall, Γ Br for skeletal tissues were greater than other tissues. In addition, Γ Br breast was 1.8261 × 10(-3) C/kg-cm(2)/MBq-h which was greater than sacrum and spongiosa bones. Moreover, according to (A release)Br of (142)Pr, the patients receiving (142)Pr do not have to be hospitalized for radiation precautions and the Bremsstrahlung production does not prevent the therapy for outpatients. However, modeling (142)Pr source in water phantom for simulation of (142)Pr source in soft tissues could be acceptable due to similarity of Γ Br in water and soft tissues; this approximation is a gross computation in the mediums encompassing high atomic numbers. These data may be practical in the investigation of Bremsstrahlung absorbed dose where (142)Pr is involved in radionuclide therapy.


The role of solidarity in social responsibility for health.
The Article focuses on the concept of social solidarity, as it is used in the Report of the International Bioethics Committee On Social Responsibility and Health. It is argued that solidarity plays a major role in supporting the whole framework of social responsibility, as presented by the IBC. Moreover, solidarity is not limited to members of particular groups, but potentially extended to all human beings on the basis of their inherent dignity; this sense of human solidarity is a necessary presupposition for a genuinely universalistic morality of justice and human rights.


Passive immunization with Leptospira LPS-specific agglutinating but not non-agglutinating monoclonal antibodies protect guinea pigs from fatal pulmonary hemorrhages induced by serovar Copenhageni challenge.
Leptospira interrogans serovar Copenhageni causes pulmonary hemorrhages with respiratory failure, a major cause of death in leptospirosis patients. Protective immunity to Leptospira is known to correlate with the production of leptospiral lipopolysaccharide (L-LPS)-specific agglutinating antibodies. We generated L-LPS-specific mouse monoclonal antibodies (MAbs) and investigated if these MAbs can protect guinea pigs against fatal pulmonary hemorrhages caused by serovar Copenhageni. The MAbs L8H4 and L9B11 against 22kDa L-LPS agglutinated leptospires and completely protected guinea pigs from the development of fatal pulmonary hemorrhages by serovar Copenhageni, whereas the MAb L4C1 against 8kDa L-LPS neither agglutinated the bacteria nor protected the animals against the fatal pulmonary hemorrhages.


Overlapping community finding with noisy pairwise constraints.
In many real applications of semi-supervised learning, the guidance provided by a human oracle might be "noisy" or inaccurate. Human annotators will often be imperfect, in the sense that they can make subjective decisions, they might only have partial knowledge of the task at hand, or they may simply complete a labeling task incorrectly due to the burden of annotation. Similarly, in the context of semi-supervised community finding in complex networks, information encoded as pairwise constraints may be unreliable or conflicting due to the human element in the annotation process. This study aims to address the challenge of handling noisy pairwise constraints in overlapping semi-supervised community detection, by framing the task as an outlier detection problem. We propose a general architecture which includes a process to "clean" or filter noisy constraints. Furthermore, we introduce multiple designs for the cleaning process which use different type of outlier detection models, including autoencoders. A comprehensive evaluation is conducted for each proposed methodology, which demonstrates the potential of the proposed architecture for reducing the impact of noisy supervision in the context of overlapping community detection.


Prokaryotic and eukaryotic integral membrane proteins have similar architecture.
Integral membrane proteins constitute a major constituent of lipid bilayer both in prokaryotes and eukaryotes. The statistical analysis was carried out to determine the bias in amino acid distribution between prokaryotic and eukaryotic integral membrane proteins (pIntMPs and eIntMPs). Our results indicate that both pIntMPs and eIntMPs demonstrate the striking similarity in amino acid distribution in their transmembrane and extramembranous region. pIntMPs have relatively greater functional importance for Gly and Asn in comparison to eIntMPs.


Effect of statins on hospitalization risk of bacterial infections in patients with or without diabetes.
To investigate whether statins reduce the risk to first hospitalization of bacterial infections, in patients with or without diabetes taking into account prior or incident comorbidities. By using administrative databases, the effect of current statin use was measured on the risk of first hospitalizations due to bacterial infections in people living in Tuscany, Italy, in the period January 1, 2011-December 31, 2015, after excluding those with previous statins use. Population was stratified as with (n = 128,207) or without diabetes (n = 3,304,906), and the hospitalization risk was analyzed by a Cox proportional hazards regression analysis after adjusting for age, gender, previous comorbidities, chronic renal failure, and prior or incident cardiovascular diseases. During the 5-year follow-up, 31,543 hospitalizations for bacterial infections were observed: 2.08(2.06-2.10) per 1000 person-year in non-diabetic and 5679: 9.13(8.94-9.32) per 1000 person-year in diabetic population. Diabetes conferred a greater risk of hospitalizations, independently from confounders [adjusted HR (95% CI) 2.04 (1.97-2.10); P < 0.0001]. Statin use decreased the risk by about 2.5% for each one month of therapy, at the same extent in subjects with or without diabetes, after adjusting for all covariates. In this population, diabetes was associated by a twofold increase in the 5-year risk of hospitalizations for bacterial infections. Statin use decreased this risk to a same extent in subjects without or with diabetes, after adjusting for main confounders including comorbidities, and previous or incident cardiovascular events.


Functional and clinical relevance of chondroitin sulfate proteoglycan 4.
The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the development of novel strategies for the management of patients with malignant melanoma. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma. For many years, T cell-based immunotherapy has been emphasized in part because of the disappointing results of the monoclonal antibody (mAb)-based clinical trials conducted in the early 1980s and in part because of the postulated major role played by T cells in tumor growth control. More recently, mAb-based therapies have gained in popularity given their clinical and commercial success for a variety of malignant diseases. As a result, there has been increased interest in identifying and characterizing antibody-defined melanoma antigens. Among them, the chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen (HMW-MAA) or melanoma chondroitin sulfate proteoglycan (MCSP), has attracted much attention in recent years because of the growing experimental evidence that it fulfills two requirements for immunotherapy to be therapeutically effective: (1) targeting of cancer stem cells (CSC) and (2) development of combinatorial therapies to counteract the escape mechanisms driven by the genetic instability of tumor cells. With this in mind, in this chapter, we have reviewed recent information related to the distribution of CSPG4 on various types of tumors, including CSC, its expression on pericytes in the tumor microenvironment, its recognition by T cells, its role in cell biology as well as the potential mechanisms underlying the ability of CSPG4-specific immunity to control malignant cell growth.


Scaling laws in cognitive sciences.
Scaling laws are ubiquitous in nature, and they pervade neural, behavioral and linguistic activities. A scaling law suggests the existence of processes or patterns that are repeated across scales of analysis. Although the variables that express a scaling law can vary from one type of activity to the next, the recurrence of scaling laws across so many different systems has prompted a search for unifying principles. In biological systems, scaling laws can reflect adaptive processes of various types and are often linked to complex systems poised near critical points. The same is true for perception, memory, language and other cognitive phenomena. Findings of scaling laws in cognitive science are indicative of scaling invariance in cognitive mechanisms and multiplicative interactions among interdependent components of cognition.


The link between aberrant splicing and B cell infiltration in breast cancer hormone therapy.
Increasing evidence has suggested alternative splicing (AS) is an essential mechanism for tumor initiation and progression. However, the functions of aberrant splicing have not been well understood in hormone therapy-treated breast cancer (HTBC) patients yet. By mining the SpliceSeq data of TCGA, we characterized 1388 survival-associated AS events (SASEs) that are markedly related to the overall survival (OS) of HTBC patients. Subsequently, a SASE prognostic signature was deduced via the least absolute shrinkage and selection operator (LASSO) and multivariate Cox analysis, and the HTBC patients were stratified into high- and low-risk groups based on the signature. The differentially expressed genes between the high- and low-risk patients were enriched with immune response genes. Furthermore, we revealed that B cell infiltration was significantly low in the high-risk patients with single-sample gene set enrichment analysis (ssGSEA), suggesting a link between AS abnormality and B cell infiltration in tumor immune microenvironment (TIME). Next, a similar prognostic signature based on splicing factor expression was deduced using Molecular Taxonomy of Breast Cancer (METABRIC) HTBC patients. When this prognostic signature was applied to stratify HTBC patients in the METABRIC and TCGA cohorts, the high-risk subgroups both had significantly low B cell infiltration in TIME. CIBERSORT analysis further demonstrated plasma cells infiltrated less in TIME. Also, both the AS (P < 0.0001) and SF (P = 0.009) prognostic signatures performed well in predicting OS of HTBC patients. In summary, our study has demonstrated that AS abnormality is a potential cause of B cell infiltration alteration, which is a critical factor for cancer death risks in HTBC patients and might be exploited therapeutically in the future.


Protective effects of selenium in tacrolimus-induced lung toxicity: potential role of heme oxygenase 1.
The present study aimed to evaluate the protective effects of selenium (Sel) administration against tacrolimus (Tac) - induced lung toxicity and to assess the relation between heme oxygenase 1 (HO-1) and these effects. The study was conducted on 36 Wistar male albino rats equally divided into four groups: (i) normal control; (ii) Sel (0.1 mg/kg per day p.o. for four weeks); (iii) TAC 3 mg/mL as single oral dose on 27th day; and (iv) Tac + Sel. Lung tissues, lung homogenate, and bronchoalveolar lavage of the sacrificed animals were investigated biochemically and histopathologically, by immunohistochemistry or by PCR. The Tac group showed significantly lower expression of HO-1. Administration of Sel was associated with increased HO-1 expression. Oxidative (malondialdehyde, reduced glutathione, superoxide dismutase, myeloperoxidase, and glutathione peroxidase activity) and nitrosative stress (nitric oxide) markers and markers of inflammation (interleukin 1β (IL-1β), IL-6, and IL-10) showed changes corresponding to HO-1 levels in rat groups. Tac group showed the highest expression of caspase-3. Sel exerted a protective role against Tac-induced lung toxicity.


FGF21 in ataxia patients with spinocerebellar atrophy and mitochondrial disease.
Serum fibroblast growth factor 21 (FGF21) was proven to be a useful biomarker for the presence of mitochondrial neuromuscular disease. In the present study, we used the difference in the serum FGF21 level to differentiate between ataxia patients with hereditary spinocerebellar atrophy (SCA-ataxia) and those with mitochondrial syndrome (Mito-ataxia). Patients with SCA-ataxia (SCA2, SCA3) and Mito-ataxia (MELAS, MERRF, LHON, maternal inherited hearing impairment mtDNA A1555G mutation) were recruited in this study. All SCA-ataxia patients revealed a consistent pattern of cerebellar atrophy. On the contrary, some of the Mito-ataxia patients exhibited a vascular lesion with cerebellar infarction. Extremely higher levels of serum FGF21 were found in the Mito-ataxia patients with MERRF and MELAS diseases, but not in patients with SCA-ataxia or LHON/mtDNA A1555G mutation. The positive trend between the mtDNA heteroplasmy and serum FGF21 was indicated in either MERRF (P=0.003, r=0.923) or MELAS (P=0.070, r=0.566) patients. Serum FGF21 can be applied as the first molecular screening among patients suspected to be victims of hereditary ataxia with neuromuscular degeneration prior to mass genetic screening.


Treatment of electronic cigarette or vaping product use-associated lung injury (EVALI) by corticosteroid and low-dose pirfenidone: Report of a case.
Electronic (e)-cigarette or vaping product use-associated lung injury (EVALI) is a novel and potentially lethal disease first reported in the United States. We report the case of a 56-year-old man who presented to our hospital with dyspnoea and cough lasting for 2 months after using an e-cigarette for approximately 50 puffs over 2 weeks. Physical examination revealed crackles in the left lower lung. High-resolution computed tomography (HRCT) showed consolidation and ground-glass opacities in both lungs. The baseline forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) were 65.7% and 63.9% of the predicted, respectively. Lung biopsy revealed organizing pneumonia with focal fibrosis. In addition to prednisolone, he was treated with a low-dose pirfenidone (200 mg three times per day) due to the persistence of a mild cough, exertional dyspnoea and basal crackles after discharge. His symptoms and FVC significantly improved, but the recovery of the DLCO was slow. The follow-up HRCT demonstrated only minimal fibrotic changes. To our knowledge, this was the first reported case of EVALI successfully treated with a combination of corticosteroid and antifibrotic agents.


Implications of a background of Hashimoto's thyroiditis on the current conservative surgical trend towards papillary thyroid carcinoma.
The purpose is to delineate the clinico-pathologic features of papillary thyroid carcinoma (PTC) occurring in a background of Hashimoto's thyroiditis (HT). A retrospective analysis of consecutive PTC patients who underwent surgery at an academic center between Jan. 2010 and Jan. 2020 was performed. The primary end point was to assess whether a background of HT implied a higher likelihood for postoperatively determined high-risk histopathologic features. Accordingly, its implication on initial surgical planning. Tumor high-risk features included aggressive histologic variants, lymphovascular invasion, extrathyroidal extension, multifocality, and positive nodal metastasis. To achieve the primary outcome of interest, a two group-designation was followed: group A (none-HT-group) and group B (HT-group). The two groups were also compared regarding postoperative complications as a secondary outcome of interest. In the specified period, 331 patients were found to have a histologically proven diagnosis of PTC. Group A accounted for 80% (265/331) of the study cohort, while group B accounted for the remainder 20%. PTC was significantly more prevalent in the absence of HT (p < 0.0001). Both groups were comparable in mean-patient-age. However, Group B demonstrated a considerably higher male:female ratio (1:10 vs. 1:3; p = 0.01). All postoperatively determined high-risk histopathologic features were comparable in both groups (p > 0.05). Nevertheless, transient hypoparathyroidism was considerably higher in group B (12% vs. 23%; p = 0.02). A background of HT does not seem to reflect a more aggressive cancerous biologic behavior. Therefore, it should not preclude the conservative surgical strategy adopted by the most recent clinical practice guidelines.


On the existence and the role of chaotic processes in the nervous system.
Chaos theory is a rapidly growing field. As a technical term, "chaos" refers to deterministic but unpredictable processes being sensitively dependent upon initial conditions. Neurobiological models and experimental results are very complicated and some research groups have tried to pursue the "neuronal chaos". Babloyantz's group has studied the fractal dimension (d) of electroencephalograms (EEG) in various physiological and pathological states. From deep sleep (d = 4) to full awakening (d > 8), a hierarchy of "strange" attractors paralles the hierarchy of states of consciousness. In epilepsy (petit mal), despite the turbulent aspect of a seizure, the attractor dimension was near to 2. In Creutzfeld-Jacob disease, the regular EEG activity corresponded to an attractor dimension less than the one measured in deep sleep. Is it healthy to be chaotic? An "active desynchronisation" could be favourable to a physiological system. Rapp's group reported variations of fractal dimension according to particular tasks. During a mental arithmetic task, this dimension increased. In another task, a P300 fractal index decreased when a target was identified. It is clear that the EEG is not representing noise. Its underlying dynamics depends on only a few degrees of freedom despite yet it is difficult to compute accurately the relevant parameters. What is the cognitive role of such a chaotic dynamics? Freeman has studied the olfactory bulb in rabbits and rats for 15 years. Multi-electrode recordings of a few mm2 showed a chaotic hierarchy from deep anaesthesia to alert state. When an animal identified a previously learned odour, the fractal dimension of the dynamics dropped off (near limit cycles).(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of a journal club on perceived barriers to the utilization of nursing research in a practice setting.
Professional accountability dictates that bedside nurses base their practice on the best available evidence from research findings. However, some staff nurses may be reluctant to read research and scholarly journals, suppressing their practice and self-development. Findings from this study suggest that perceptions of barriers to research utilization in practice may decrease through the use of unit-based journal clubs. The staff development educator can play a pivotal role in nursing practice progression by implementing journal clubs.


Quantitative Determination and Imaging of Gαq Signaling in Live Cells via Split-Luciferase Complementation.
G Protein-coupled receptors (GPCRs) transduce signals elicited by bioactive chemical agents (ligands), such as hormones, neurotransmitters, or cytokines, across the cellular membrane. Upon ligand binding, the receptor undergoes structural rearrangements, which cause the activation of G proteins. This triggers the activation of signaling cascades involving amplification, which takes place after every stage of the cascade. Consequently, signals from early stages can be masked when the activation of the signaling cascade is probed remote (distal) from the receptor. This led to the development of several techniques, which probe the activation of such signaling cascades as proximal to the receptor as possible. However, these methods often require specialized equipment or are limited in throughput. By applying split-luciferase complementation to the interaction between the Gαq protein and its effector the phospholipase C-β3 (PLC-β3), we introduce a protocol with a conventional plate reader at high throughput. The method is applicable to live cells and additionally allows imaging of the probe by bioluminescence microscopy.


Association between endoscopic findings related to colonic diverticula and bowel habits: A multicenter study in Japan.
Few studies have shown the associations between colonic diverticula and endoscopic findings such as location, inflammation, number of diverticula, sigmoid colon rigidity, and bowel habits. Japanese subjects who underwent total colonoscopies at six centers in Japan from November 2015 to October 2016 were analyzed. Bowel habits were evaluated using the Gastrointestinal Symptom Rating Scale. Location and number of diverticula, inflammation, and sigmoid colon rigidity were evaluated from endoscopy results. A total of 762 subjects (486 men and 276 women [ratio, 1.76:1]) whose mean age was 65.5 ± 11.4 years were evaluated. In multivariate analysis, presence of constipation was associated with a significantly lower likelihood of left-sided colonic diverticula (odds ratio = 0.40, 95% confidence interval 0.20-0.82, P = 0.012), whereas right-sided and bilateral-sided colonic diverticula, multiple colonic diverticula, inflammation findings, and sigmoid colon rigidity were not related to bowel habits. Among endoscopic findings related to colonic diverticula and bowel habits, only left-sided colonic diverticula were inversely associated with constipation, whereas inflammation findings, multiple diverticula, and sigmoid colon rigidity were not related to bowel habits. However, the association of inflammation findings with colonic diverticula and bowel habits should be further studied. Investigation of changes in left-sided colonic diverticula may lead to new treatments for constipation.


Indications for and timing of delivery in diabetic pregnancies.
The management of 430 diabetic pregnancies is presented. Our protocol emphasized "tight" metabolic control and assessment of fetal well-being by antepartum fetal heart rate testings and estriol levels. Spontaneous labor was allowed in uncomplicated Class A diabetic patients. Labor in complicated cases and insulin-dependent diabetic pregnancies was induced after establishing fetal lung maturity, except when a maternal or fetal complication dictated otherwise. A significant drop in estriol was observed in 4% of Class A diabetic patients and 10.2% of insulin-dependent diabetic patients. None developed a positive contraction stress test. Abnormal fetal well-being tests contributed minimally to the indications for induction of labor. The incidence of induced preterm delivery was 2.8% in Class A diabetic patients and 18.4% in insulin-dependent diabetic ones. The perinatal mortality was 5.6:1000 and 13:1000, respectively. The incidence of respiratory distress syndrome was very low, and none of the cases were associated with a "mature" amniotic fluid lecithin phosphorus measurement.


Rumen Fluke in Great Britain.
Calicophoron daubneyi is the primary rumen fluke (RF) found in Europe in ruminants and infection is more common in cattle than in sheep. The incidence of RF has appeared to increase greatly throughout Europe in the last 10-15 years, with outbreaks of clinical paramphistomosis confirmed in ruminants in many countries, including Great Britain and Ireland. Clinical disease, due to immature stages developing in the small intestine, appears infrequently but can occur, usually in the autumn or winter within weeks of beginning to graze wet pasture. Although disease due to adult RF has not been proven, subclinical production losses have been attributed to adult RF infection by some researchers. As the intermediate host for RF and the liver fluke (Fasciola hepatica) is the mud snail (Galba truncatula), similar habitats and environmental conditions favour both parasites. There may, however, be differences in parasite development and interactions within both the final and intermediate hosts. No anthelminthic product is licensed for treatment of ruminants for RF in the UK. However, oxyclozanide, licensed for the treatment of adult F. hepatica infection, has been shown to have activity, but it may be more effective against the adult than the immature stages. The future prevalence of RF due to climate change and limited treatment options is unpredictable. Infection and clinical disease could become more common and RF is worthy of further research.


Direct Growth of Highly Conductive Large-Area Stretchable Graphene.
The direct synthesis of inherently defect-free, large-area graphene on flexible substrates is a key technology for soft electronic devices. In the present work, in situ plasma-assisted thermal chemical vapor deposition is implemented in order to synthesize 4 in. diameter high-quality graphene directly on 10 nm thick Ti-buffered substrates at 100 °C. The in situ synthesized monolayer graphene displays outstanding stretching properties coupled with low sheet resistance. Further improved mechanical and electronic performances are achieved by the in situ multi-stacking of graphene. The four-layered graphene multi-stack is shown to display an ultralow resistance of ≈6 Ω sq-1, which is consistently maintained during the harsh repeat stretching tests and is assisted by self-p-doping under ambient conditions. Graphene-field effect transistors fabricated on polydimethylsiloxane substrates reveal an unprecedented hole mobility of ≈21 000 cm2 V-1 s-1 at a gate voltage of -4 V, irrespective of the channel length, which is consistently maintained during the repeat stretching test of 5000 cycles at 140% parallel strain.


Exercise training counteracts urothelial carcinoma-induced alterations in skeletal muscle mitochondria phospholipidome in an animal model.
Cancer associated body wasting is the cause of physical disability, reduced tolerance to anticancer therapy and reduced survival of cancer patients and, similarly to cancer, its incidence is increasing. There is no cure for this clinical condition, and the pathophysiological process involved is largely unknown. Exercise training appears as the gold standard non-pharmacological therapy for the management of this wasting syndrome. Herein we used a lipidomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS) to study the effect of exercise in the modulation of phospholipids profile of mitochondria isolated from gastrocnemius muscle of a pre-clinical model of urothelial carcinoma-related body wasting (BBN induced), submitted to 13 weeks of treadmill exercise after diagnosis. Multivariate analysis showed a close relationship between the BBN exercise group and both control groups (control sedentary and control exercise), while the BBN sedentary group was significantly separated from the control groups and the BBN exercise group. Univariate statistical analysis revealed differences mainly in phosphatidylserine (PS) and cardiolipin (CL), although some differences were also observed in phosphatidylinositol (PI, LPI) and phosphatidylcholine (PC) phospholipids. PS with shorter fatty acyl chains were up-regulated in the BBN sedentary group, while the other species of PS with longer FA and a higher degree of unsaturation were down-regulated, but the BBN exercise group was mostly similar to control groups. Remarkably, exercise training prevented these alterations and had a positive impact on the ability of mitochondria to produce ATP, restoring the healthy phospholipid profile. The remodelling of mitochondria phospholipid profile in rats with urothelial carcinoma allowed confirming the importance of the lipid metabolism in mitochondria dysfunction in cancer-induced skeletal muscle remodelling. The regulation of phospholipid biosynthetic pathways observed in the BBN exercise group supported the current perspective that exercise is an adequate therapeutic approach for the management of cancer-related muscle remodeling.


Probability intervals of toxicity and efficacy design for dose-finding clinical trials in oncology.
Immunotherapy, gene therapy or adoptive cell therapies, such as the chimeric antigen receptor+ T-cell therapies, have demonstrated promising therapeutic effects in oncology patients. We consider statistical designs for dose-finding adoptive cell therapy trials, in which the monotonic dose-response relationship assumed in traditional oncology trials may not hold. Building upon a previous design called "TEPI", we propose a new dose finding method - Probability Intervals of Toxicity and Efficacy (PRINTE), which utilizes toxicity and efficacy jointly in making dosing decisions, does not require a pre-elicited decision table and at the same time can handle Ockham's razor properly in the statistical inference. We show that optimizing the joint posterior expected utility of toxicity and efficacy under a 0-1 loss is equivalent to maximizing the marginal model posterior probability in the two-dimensional probability space. An extensive simulation study under various scenarios are conducted and results show that PRINTE outperforms existing designs in the literature since it assigns more patients to optimal doses and less to toxic ones, and selects optimal doses with higher percentages. The simple and transparent features together with good operating characteristics make PRINTE an improved design for dose-finding trials in oncology trials.