Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose.
Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clinical trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clinical trials. The MRDD is an estimated upper dose limit beyond which a drug's efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicological) or undesirable pharmacological effects are observed. The NOAEL in test animals is currently used to estimate the safe starting dose in human clinical trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chemicals in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topological descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74-78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of +/-10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clinical trials with the addition of a 10-fold safety factor. For non-pharmaceutical chemicals any compound-related effect can be considered an undesirable and adverse toxicological effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.


Severe craniofacial sclerosis with multiple anomalies in a boy and his mother.
A boy is described with severe hyperostosis of the cranium and facial bones, and many other abnormalities including macrocephaly, abnormal facies, cleft palate, conductive hearing loss, speech defect, dental and digital anomalies, delayed skeletal development, short fibulas, short stature of postnatal onset, cervical kyphosis, and progressive lumbar lordosis. His mother exhibited craniofacial sclerosis, similar dental defects, and mild osteopathia striata without other abnormalities. This family may represent a previously undescribed inherited syndrome with cranial sclerosis.


Sodium colistimethate loaded lipid nanocarriers for the treatment of Pseudomonas aeruginosa infections associated with cystic fibrosis.
Lung impairment is the most life-threatening factor for cystic fibrosis patients. Indeed, Pseudomonas aeruginosa is the main pathogen in the pulmonary infection of these patients. In this work, we developed sodium colistimethate loaded lipid nanoparticles, namely, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), as a strategy to enhance the antimicrobial therapy against P. aeruginosa in cystic fibrosis patients. The nanoparticles obtained displayed a 200-400 nm size, high drug entrapment (79-94%) and a sustained drug release profile. Moreover, both SLN and NLC presented antimicrobial activity against clinically isolated P. aeruginosa. The integrity of the nanoparticles was not affected by nebulization through a mesh vibrating nebulizer. Moreover, lipid nanoparticles appeared to be less toxic than free sodium colistimethate in cell culture. Finally, an in vivo distribution experiment showed that nanoparticles spread homogenously through the lung and there was no migration of lipid nanoparticles to other organs, such as liver, spleen or kidneys.


A study of the effects of lamotrigine on mice using two convulsive tests.
The AIM was to study the effects of lamotrigine on bicuculline and pentylenetetrazol models of epilepsy. Mice divided in 8 groups (n = 6) were pretreated intraperitoneally 30 min before pentylenetetrazol (50 mg/kg) or bicuculline (1 mg/kg) with saline 0.1 ml/10 g body weight or lamotrigine 10 mg/kg, 15 mg/kg or 20 mg/kg, respectively. The seizure intensity and latency to the seizures 60 min after bicuculline or pentylenetetrazol injection were observed. The following scale for seizure intensity was used: 1 - excitation; 2 - body tremor; 3 - clonic seizures of forelimbs; 4 - heavy clonic seizures with rotations; 5 - tonic seizures of forelimbs; 6 - tonic seizures of limbs. The controls showed bicuculline-induced seizure intensity up to 5. Lamotrigine in the higher doses used decreased the seizure intensity (p <0.05). Lamotrigine in all doses studied did not change the latency period of the first bicuculline seizure compared with the control. Controls treated with pentylenetetrazol showed seizure intensity up to 4. Lamotrigine in the highest dose decreased the pentylenetetrazol-induced seizure intensity (p < 0.05). Lamotrigine in all studied doses increased the latency to the first pentylenetetrazol-induced seizure compared with the controls (p < 0.05). Both convulsing drugs influence the brain GABA-ergic transmitter system by competitively blocking GABAA receptors. Lamotrigine inhibits glutamate transmission and sodium channels. Both neurotransmissions - glutamate and GABA are closely related in seizure control. The CONCLUSION is that lamotrigine has an anticonvulsive effect on both bicuculline and pentylenetetrazol seizure models, suppressing seizure intensity and influencing the latency to the first seizure.


A comparison of leukocyte ascorbate levels measured by the 2,4-dinitrophenylhydrazine method with high-performance liquid chromatography using electrochemical detection.
In leukocytes a dynamic relationship between the reduced form of ascorbic acid (AA) and its oxidized product dehydro-AA has been described. It is therefore important to know which form of the vitamin predominates when choosing a methodology. The purpose of this study was to find out if the majority of ascorbate in human leukocytes isolated by centrifugation through Percoll is in the reduced AA form by measuring reduced AA by HPLC and comparing the values to those obtained by using the 2,4-dinitrophenylhydrazine (DNPH) method which measures total ascorbate, and quantifying the reduced and oxidized forms of the vitamin in leukocytes using a modification of the DNPH method. There was no significant difference (P greater than .05) between the HPLC and DNPH values for 12 individuals and 87% of the AA was found to be in the reduced form. These results support the assumption that the majority of AA found in a mixed leukocyte population isolated through Percoll is in the reduced form and that both methods can be used for AA measurements.


Growth inhibition of cultured marine phytoplankton by toxic algal-derived polyunsaturated aldehydes.
Several marine diatoms produce polyunsaturated aldehydes (PUAs) that have been shown to be toxic to a wide variety of model organisms, from bacteria to invertebrates. However, very little information is available on their effect on phytoplankton. Here, we expand previous studies to six species of marine phytoplankton, belonging to different taxonomic groups that are well represented in marine plankton. The effect of three PUAs, 2E,4E-decadienal, 2E,4E-octadienal and 2E,4E-heptadienal, was assessed on growth, cell membrane permeability, flow cytometric properties and morphology. A concentration-dependent reduction in the growth rate was observed for all cultures exposed to PUAs with longer-chained aldehydes having stronger effects on growth than shorter-chained aldehydes. Clear differences were observed among the different species. The prymnesiophyte Isochrysis galbana was the most sensitive species to PUA exposure with a lower threshold for an observed effect triggered by mean concentrations of 0.10 micromol L(-1) for 2E,4E-decadienal, 1.86 micromol L(-1) for 2E,4E-octadienal and 3.06 micromol L(-1) for 2E,4E-heptadienal, and a 50% growth inhibition (EC(50)) with respect to the control at 0.99, 2.25 and 5.90 micromol L(-1) for the three PUAs, respectively. Alternatively, the chlorophyte Tetraselmis suecica and the diatom Skeletonema marinoi (formerly S. costatum) were the most resistant species with 50% growth inhibition occurring at concentrations at least two to three times higher than I. galbana. In all species, the three PUAs caused changes in flow cytometric measures of cell size and cell granulosity and increased membrane permeability, assessed using the viability stain SYTOX Green. For example, after 48 h 51.6+/-2.6% of I. galbana cells and 15.0+/-1.8% of S. marinoi cells were not viable. Chromatin fragmentation was observed in the dinoflagellate Amphidinium carterae while clear DNA degradation was observed in the chlorophyte Dunaliella tertiolecta. Concentrations used are in a significant range for affecting growth and performance of phytoplankton living in close vicinity of PUA-producing algae. Thus, PUAs may act as allelochemicals by mediating interactions among planktonic organisms.


Intermittent micro-aeration: New strategy to control volatile fatty acid accumulation in high organic loading anaerobic digestion.
This study developed an intermittent oxidation-reduction potential (ORP)-controlled micro-aeration system for high solids anaerobic digestion (AD) of lignocellulosic biomass without volatile fatty acids (VFA) accumulation at high organic loading rate (OLR). Traditional AD of Napier grass, a model lignocellulosic biomass, at an OLR of 5 g volatile solids (VS)/L/day resulted in an accumulation of total VFA concentration up to 9.2 g/L as acetic acid (HAc) equivalent, causing rapid drops in pH and methane yield, and driving the digester to the verge of failure. Once intermittent (every 24 h) ORP-controlled micro-aeration (at ORP of -470 mV) was initiated, the total VFA concentration rapidly decreased to 3.0 g HAc/L and the methane yield improved, resulting in stable digester performance without the need for alkalinity supplementation or OLR reduction. By combining reactor performance results, mass balance analyses, microbial community characterization data, and a bioenergetic evaluation, this study suggested that rapid VFA conversion and CH4 production were carried out by facultative anaerobes and hydrogenotrophic methanogens under micro-aerobic conditions. This novel operating approach can be applied as an effective control strategy for high OLR AD processes especially in the event of VFA accumulation.


Expression of immune checkpoint molecules programmed death protein 1, programmed death-ligand 1 and inducible T-cell co-stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome.
The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL. The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T-cell co-stimulator (ICOS) and programmed death-ligand 1 (PD-L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival. This consecutive case series enrolled 47 patients: 57% had stage IA-IIA disease and 43% had stage IIB-IVA2 disease (including seven with SS). PD1, PD-L1 and ICOS expression was seen in all biopsies. Notably, PD-L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD-L1 was associated with advanced-stage disease (P = 0·007 for both) and with the appearance of large-cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD-L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD-L1 and ICOS) was associated with advanced-stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014). These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD-L1 in advanced disease.


Dynamic training of a novelty classifier algorithm for real-time detection of early seizure onset.
To develop an adaptive framework for seizure detection in real-time that is practical to use in the Epilepsy Monitoring Unit (EMU) as a warning signal, and whose output helps characterize epileptiform activity. Our algorithm was tested on intracranial EEG from epilepsy patients admitted to the EMU for presurgical evaluation. Our framework uses a one-class Support Vector Machine (SVM) that is being trained dynamically according to past activity in all available channels to classify the novelty of the current activity. In this study we compared multiple configurations using a one-class SVM to assess if there is significance over specific neural features or electrode locations. Our results show that the algorithm reaches a sensitivity of 87% for early-onset seizure detection and of 97.7% as a generic seizure detection. Our algorithm is capable of running in real-time and achieving a high performance for early seizure-onset detection with a low false positive rate and robustness in detection of different type of seizure-onset patterns. This algorithm offers a solution to warning systems in the EMU as well as a tool for seizure characterization during post-hoc analysis of intracranial EEG data for surgical resection of the epileptogenic network.


Formation of liquid crystalline phase of actin filament solutions and its dependence on filament length as studied by optical birefringence.
We studied the formation and structure of liquid crystalline phase of F-actin solutions by polarized light photometry, assuming that a small domain of the liquid crystalline phase works as a linear retardation plate. Transmittance of polarized light due to the birefringence of liquid crystalline phase appeared above a threshold concentration of F-actin. The threshold increased with a decrease in filament length, which was regulated by calcium-activated gelsolin. The intensity increased linearly with increasing concentrations until it reached a stationary value. The deviation of optical axis direction of the putative retardation plate was estimated 7-15 degrees. These results indicate that:(a) the liquid crystalline phase is formed above a threshold concentration of F-actin; (b) the threshold is proportional to the inverse of filament length; (c) the ordered phase coexists with the isotropic one, increasing the volume fraction with increasing concentrations until all filaments take the liquid crystalline structure; (d) the filaments in liquid crystalline phase take a highly ordered array. These results can be attributed to the excluded volume effect of rod-like molecules on the formation of liquid crystalline structure.


Compositional biases and evolution of the largest plant RNA virus order Patatavirales.
Patatavirales is the largest order of plant RNA viruses and exclusively contains the family Potyviridae, accounting for 30 % of all known plant viruses. The composition bias of animal RNA viruses and several plant RNA viruses has been determined. However, the comprehensive nucleic acid composition, codon pair usage patterns, dinucleotide preference and codon pair preference of plant RNA viruses have not been investigated to date. In this study, integrated analysis and discussion of the nucleic acid composition, codon usage patterns, dinucleotide composition and codon pair bias of potyvirids were performed using 3732 complete genome coding sequences. The nucleic acid composition of potyvirids was significantly enriched in A/U. Interestingly, the A/U-rich nucleotide composition of Patatavirales is essential for determining the preferred A-ended and U-ended codons and the overexpression of UpG and CpA dinucleotides. The codon usage patterns and codon pair bias of potyvirids were significantly correlated with their nucleic acid composition. Additionally, the codon usage pattern, dinucleotide composition and codon-pair bias of potyvirids are more dependent on the classification of the virus compared with their hosts. Our analysis provides a better understanding of future research on the origin and evolution patterns of the order Patatavirales.


Understanding low chemoprevention uptake by women at high risk of breast cancer: findings from a qualitative inductive study of women's risk-reduction experiences.
Chemoprevention is one of several methods that have been developed to help high-risk women reduce their risk of breast cancer. Reasons for the low uptake of chemoprevention are poorly understood. This paper seeks a deeper understanding of this phenomenon by drawing on women's own narratives about their awareness of chemoprevention and their risk-related experiences. This research is based on a parent project that included fifty in-depth, semi-structured interviews with a purposive sample of African American and White women at elevated risk of breast cancer. This specific study draws on the forty-seven interviews conducted with women at high or severe risk of breast cancer, all of whom are eligible to use chemoprevention for breast cancer risk-reduction. Interviews were analyzed using grounded theory methods. Forty-five percent of participants, and only 21% of African American participants, were aware of chemoprevention options. Women who had seen specialists were more likely to be aware, particularly if they had ongoing specialist access. Aware and unaware women relied on different types of sources for prevention-related information. Those whose main source of information was a healthcare provider were more likely to know about chemoprevention. Aware women used more nuanced information gathering strategies and worried more about cancer. Women simultaneously considered all risk-reduction options they knew about. Those who knew about chemoprevention but were reluctant to use it felt this way for multiple reasons, having to do with potential side effects, perceived extreme-ness of the intervention, similarity to chemotherapy, unknown information about chemoprevention, and reluctance to take medications in general. Lack of chemoprevention awareness is a critical gap in women's ability to make health-protective choices. Future research in this field must consider complexities in both women's perspectives on chemoprevention and the reasons they are reluctant to use it.


Education interventions in Chinese cardiac patients on health behaviours, disease-related knowledge, and health outcomes: A systematic review and meta-analysis.
This systematic review and meta-analysis aimed to summarize and synthesize the available evidence in adult Chinese cardiac patients to determine the effect of education interventions on health behaviours, disease-related knowledge, self-efficacy, depressive symptoms, anxiety symptoms, health-related quality of life, morbidity, and mortality. Seven databases were searched from database inception until January 2020 for randomized controlled trials. Characteristics of education interventions were described and random-effects meta-analysis was performed where feasible. Overall, 18 randomized controlled trials were included in this systematic review and suggested that education interventions are effective in improving patients' physical activity, dietary habits, medication behaviour, disease-related knowledge, and health-related quality of life. Meta-analysis of two studies demonstrated benefit on physical activity (standardized mean difference [SMD] 1.27, 95% confidence interval [CI] 1.06-1.48; participants = 422; I2 = 0%), dietary habits (SMD 0.76, 95%CI 0.44-1.08; participants = 422; I2 = 61%), and medication behaviour (mean difference [MD] 0.31, 95%CI 0.17-0.46; participants = 422; I2 = 28%). This study supports the benefits of education interventions for adult Chinese cardiac patients on health behaviours, disease-related knowledge, and health-related quality of life. Future studies should characterize their education interventions in detail to facilitate reproducibility and comparison. This study identified the need for studies on the outcome of alcohol consumption and in Chinese immigrant populations.


The diagnostic accuracy of carbohydrate-deficient transferrin, sialic acid and commonly used markers of alcohol abuse during abstinence.
The normalization of alcohol abuse markers during the abstinence depends on the time since the last drinking. The aim of this study was to evaluate the diagnostic accuracy (area under the curve-AUC, sensitivity and specificity) of CDT, sialic acid and others biochemical and hematological markers of chronic alcohol abuse during abstinence. We studied 75 patients admitted to the treatment of alcohol dependence. The blood samples were collected upon admission to the hospital. CDT was estimated using an immunoturbidimetric assay after anion-exchange chromatography and sialic acid by enzymatic colorimetric method. Mean values of all markers were significantly higher. All tests, except SA, negatively correlated with time of abstinence but not with age, duration of dependence and amounts of weekly alcohol consumption. The area under the curve (AUC) for all tested markers decreased progressively during the abstinence. The highest AUC was obtained for CDT (0.98) and the lowest for ALT (0.78) when alcohol was consumed in the last week. AUC for sialic acid was lower than of CDT but higher than of ALT. We conclude that the diagnostic accuracy for tested laboratory markers depends on the self-reported time of abstinence being the highest for CDT in the first week of abstinence. The accuracy of sialic acid was observed between GGT and ALT.


Resistance of experientially-induced changes in murine plus-maze behaviour to altered retest conditions.
Prior exposure to the elevated plus-maze results in profound behavioural alterations in rats and mice, with 24 h retest profiles indicative of fear sensitization. The present study was designed to examine the influence of retest cues on this phenomenon in male DBA/2 mice. Results confirmed the potent influence of prior maze experience on subsequent behavioural patterns, and showed that this was not affected by manipulations of extra-maze cues (90 degrees re-orientation of the maze or use of a different laboratory) on Trial 2. Data are discussed in relation to experientially-induced shifts in behavioural strategy and the apparent involvement of simple proximal cues (probably thigmotactic) in this enduring and adaptive form of spatial learning.


Effects of deep transcranial magnetic stimulation (dTMS) on cognition.
Deep transcranial magnetic stimulation (dTMS) is a modern non-invasive brain stimulation method demonstrated as effective in the treatment of major depression and obsessive-compulsive disorder (OCD). This review aims to survey present knowledge concerning the cognitive function changes identified in dTMS research. A systematic literature search in PubMed and Google Scholar was performed and 23 out of 64 studies on dTMS and cognitive functioning were included in the review. Ten studies were conducted with patients with affective disorders, six with healthy participants, two with schizophrenia patients, two with OCD patients, and one study each with patients suffering from central neuropathic pain, autistic disorder, and attention deficit hyperactivity disorder. The best outcomes were obtained after 20 sessions of high-frequency dTMS with OCD patients, where, in addition to clinical improvement, patients showed amelioration of cognitive functions, specifically in cognitive control domains. The studies on patients with depression appear to show inconsistent results, from cognitive improvement in open-label studies to no improvement versus sham dTMS in controlled trials. Experimental research in healthy volunteers suggests an influence of dTMS on memory and self-agency, and also contain contradictory results. Most studies did not demonstrate a significant improvement in cognitive functioning. However, randomized sham-controlled trials with larger groups of medication-free patients and inclusion of functional imaging or electrophysiological recording connected with dTMS application are necessary for more detailed and confident conclusions concerning the effect of dTMS on cognitive functions.


Symptom prescription: inducing anxiety by 70% exhalation.
This study investigates the effects of partial exhalation to feelings of anxiety. Thirty five volunteer subjects (14 male, 21 female, mean age 40.6) were first trained in slow diaphragmatic breathing (SDB). Then subjects rated their anxiety levels on a scale from 1 (none) to 5 (extreme) in sequential conditions of SDB, 70% subjective exhalation, and SDB. During the 70% subjective exhalation phase, subjects were instructed to breathe and limit their exhalation to 70% of the inhaled volume during each consecutive breath. The 70% subjective condition significantly (P < .0005) increased subjects' anxiety levels as compared to the initial SDB baseline, while a return to SDB significantly reduced the anxiety levels. The 70% approach appears useful in demonstrating to the client that possible changes in breathing patterns can affect anxiety.


Construction, petro-collecting/dispersing capacities, antimicrobial activity, and molecular docking study of new cationic surfactant-sulfonamide conjugates.
Surfactants with their diverse activities have been recently involved in controlling the spread of new coronavirus (COVID-19) pandemic as they are capable of disrupting the membrane surrounding the virus. Using hybrids approach, we constructed a novel series of cationic surfactant-sulfonamide conjugates (3a-g) through quaternization of the as-prepared sulfonamide derivatives (2a-g) with n-hexadecyl iodide followed by structural characterization by spectroscopy (IR and NMR). Being collective properties required in petroleum-processing environment, the petro-collecting/dispersing capacities on the surface of waters with different degrees of mineralization, and the antimicrobial performance against microbes and sulfate-reducing bacteria (SRB) that mitigate microbiological corrosion were investigated for the synthesized conjugates. Among these conjugates, 3g (2.5% aq. solution) exhibited the strongest ability to disperse the thin petroleum film on the seawater surface, whereas KD is 95.33% after 96 h. In diluted form, 3f collected the petroleum layer on distilled water surface (Kmax = 32.01) for duration exceeds 4 days. Additionally, almost all compounds revealed high potency and comparable action with standard antimicrobials, especially 3b and 3f, which emphasize their role as potential biocides. Regarding biocidal activity against SRB, 3g causes a significant reduction in the bacterial count from 2.8 × 106 cells/mL to Nil. Moreover, the conducted molecular docking study confirms the strong correlation between RNA polymerase binding with bioactivity against microbes over other studied proteins (threonine synthase and cyclooxygenase-2).


What can S-shaped potential profiles tell us about the mechanism of membrane potential generation?
Membrane theory attributes the generation mechanism of the membrane potential to transmembrane ion transport, while Cheng's ISE (Ion selective electrode) mechanism attributes the ISE potential generation to ion adsorption on to the ISE surface. Although the membrane potential generation mechanism is different from the ISE potential generation mechanism, both the membrane potential and the ISE potential exhibit quite similar characteristics. For instance, both become indifferent to the variation of the ion concentration in both the high and the low ion concentration environment. Our experimental and theoretical investigations suggest that such a characteristic membrane potential behavior could be explained by the ion adsorption mechanism called Ling's adsorption theory (LA theory) instead of by membrane theory. If the membrane potential generation mechanism is explained by the LA theory, then the significant similarity between the membrane potential and the ISE potential is understandable, since both the LA theory and Cheng's ISE mechanism rely on the ion adsorption process. Although the LA theory is not acknowledged as the mechanism for the membrane potential generation in the mainstream physiology community, it does not have any serious defect in principle as a membrane potential generation mechanism. Hence, it is worth investigating if the current membrane potential generation mechanism needs reevaluation in light of evidence presented here. We conclude that the LA theory is a quite plausible membrane potential generation mechanism, suggesting that it may contribute to it.


Protective role of TIRAP functional variant against development of coronary artery disease.
Coronary artery disease (CAD) is the leading cause of sudden death worldwide. Inflammation is proved to be an important player in development of the CAD. Inflammation is directly regulated by the Toll like receptors (TLRs). Susceptibility of CAD is influenced by genetic variations within TLRs and the proteins involved in its signaling cascade. The TIRAP/MAL {TIR domain containing adaptor protein / MyD88 (myeloid differentiation primary response gene 88) adaptor-like} exhibits maximum genetic variations of all adaptor proteins involved in TLR signaling cascade. Susceptibility to a number of diseases can be influenced due to presence of S180L single nucleotide polymorphism (SNP) of TIRAP/MAL. This study was conducted to investigate the functional role of this well characterized S180L polymorphism on susceptibility to CAD among Pakistani patients. A total of 146 Pakistani CAD patients and 147 controls were genotyped by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) and the data was analyzed by using 2-tailed Chi square (x2 ) test. The p value ≤ 0.05 was considered to be significant. Significantly high frequency of homozygous L180L genotype was observed among healthy subjects as compared to the CAD patients [24 (16%) vs 7 (5%); x2 11.85; p = 0.003]. Moreover, the allele frequency of the minor allele; 180L was observed to be significantly higher among controls than the CAD patients, having same direction of association [156 (53%) vs 131 (45%); OR (95% CI) = 0.7198 (0.520-0.996); p < 0.05). Our results indicate that protective effect of L180L; a coding variant of TIRAP/MAL against CAD is discernible.


Long-term effectiveness and safety of didanosine combined with lamivudine and efavirenz or nevirapine in antiretroviral-naive patients: a 9-year cohort study in Senegal.
The use of didanosine (ddI) in first-line antiretroviral therapy has been recently promoted for resource-limited settings. We therefore compared the long-term effectiveness and safety of the regimen combining ddI, lamivudine, and efavirenz or nevirapine with that of the WHO-recommended regimen of zidovudine (ZDV), lamivudine, and efavirenz or nevirapine in antiretroviral-naïve patients in Senegal. Observational cohort study of patients enrolled between January 2000 and April 2002 in the Senegalese antiretroviral drug access initiative. Multivariate analyses were performed to compare, between the ddI and ZDV groups, the proportion of patients with a viral load <500 copies/ml during follow-up; the increase in the CD4 cell count; survival; treatment changes and severe adverse events. Of 151 patients, 71 received the ddI-based treatment and 80 received the ZDV-based treatment. Throughout follow-up, 80-95% of patients had a viral load below 500 copies/ml in both the ddI and ZDV groups (P = 0.5). The CD4 cell count increased after treatment initiation from 176 to 497 cells/mm(3) in the ddI group and from 176 to 567 cells/mm(3) in the ZDV group (P > 0.3). The rate of death tended to be higher in the ddI group (P = 0.06). ddI was less commonly discontinued than ZDV (P = 0.03). The combination of ddI, lamivudine, and efavirenz or nevirapine resulted in sustained viral suppression and immunological recovery.


Anticancer effects of an extract from a local planarian species on human acute myeloid leukemia HL-60 cells in vitro.
Current anti-cancer drugs can cause many undesirable side effects to patients. Thus, there is a constant need to develop alternative therapeutic drugs. Bioactive compounds derived from natural products including animals, plants and microorganisms are being actively studied as sources for anticancer treatments. Freshwater planarians are important models for stem cell research and regeneration. However, to date, no studies on the biological activities of planaria extracts on cancer have been published. The aim of this study was to examine the potential antitumoral activity of the extract from planaria species-Malta (PSM) on human acute myeloid leukemia (AML) HL-60 cells. Antiproliferative activity was studied in terms of proliferation, apoptosis and differentiation. The expression of genes involved in the regulation of these important cellular processes was also analyzed using real-time PCR. PSM extract exhibited a selective cytotoxic effect on HL-60 cells when compared to normal lymphocytes. Furthermore, cell cycle analysis and Annexin V/PI assay showed that the extract induced apoptosis in HL-60 cells. The PSM extract induced myeloid differentiation with HL-60 cells showing a decreased nucleo/cytoplasmic ratio, an increase in nitroblue tetrazolium-positive cells, and CD11b- and CD14-positive cells. Finally, we also found that the PSM extract increased the expression of CEBPA, CEBPB, CEBPE, SPI1, BAX, CDKN1A and CDKN2C; whereas it reduced the expression of c-MYC and BCL2. This is the first study to reveal the antiproliferative, cytotoxic, and differentiation potential of PSM on HL-60 cells and suggests that it may have considerable potential for development as a novel natural product-based anticancer agent against AML.


Unlocking the potential of TIPS placement as a bridge to elective and emergency surgery in cirrhotic patients: a meta-analysis and future directions for endovascular resuscitation in acute care surgery.
In this systematic review and meta-analysis, we examined the evidence on transjugular intrahepatic portosystemic shunt (TIPS) as a bridge to elective and emergency surgery in cirrhotic patients. We aimed to assess the perioperative characteristics, management approaches, and outcomes of this intervention, which is used to achieve portal decompression and enable the safe performance of elective and emergent surgery. MEDLINE and Scopus were searched for studies reporting the outcomes of cirrhotic patients undergoing elective and emergency surgery with preoperative TIPS. The risk of bias was evaluated using the methodological index for non-randomized studies of interventions, and the JBI critical appraisal tool for case reports. The outcomes of interest were: 1. Surgery after TIPS; 2. Mortality; 3. Perioperative transfusions; and 4. Postoperative liver-related events. A DerSimonian and Laird (random-effects) model was used to perform the meta-analyses in which the overall (combined) effect estimate was presented in the form of an odds ratio (summary statistic). Of 426 patients (from 27 articles), 256 (60.1%) underwent preoperative TIPS. Random effects MA showed significantly lower odds of postoperative ascites with preoperative TIPS (OR = 0.40, 95% CI 0.22-0.72; I2 = 0%). There were no significant differences in 90-day mortality (3 studies: OR = 0.76, 95% CI 0.33-1.77; I2 = 18.2%), perioperative transfusion requirement (3 studies: OR = 0.89, 95% CI 0.28-2,84; I2 = 70.1%), postoperative hepatic encephalopathy (2 studies: OR = 0.97, 95% CI 0.35-2.69; I2 = 0%), and postoperative ACLF (3 studies: OR = 1.02, 95% CI 0.15-6.8, I2 = 78.9%). Preoperative TIPS appears safe in cirrhotic patients who undergo elective and emergency surgery and may have a potential role in postoperative ascites control. Future randomized clinical trials should test these preliminary results.


Changes in nationwide Medicare and Medicaid expenditures on lipid-lowering therapies after proprotein convertase/subtilisin type 9 inhibitor availability.
Several advances in lipid-lowering pharmacotherapy and changes in generic formulation availability occurred between 2013 and 2017. We sought to examine nationwide trends in Medicare Part D and Medicaid expenditures on lipid-lowering therapies from 2013 to 2017. We aggregated 662.2 million Medicare Part D and Medicaid prescription claims with associated expense data for 2013 to 2017 from the Medicare and Medicaid Drug Spending Dashboards for nine therapeutic classes of lipid-lowering therapies. Total Medicare Part D expenditures on lipid-lowering therapies was $7.01 billion in 2013 and $5.07 billion in 2017. Total Medicaid lipid-lowering therapy expenditures decreased from $440.9 million in 2013 to $398.7 million in 2017. Annual Medicare expenditures on Crestor were $2.2 billion in 2013 and $0.31 billion in 2017. Annual Medicaid Crestor expenditures decreased from $92.4 million in 2013 to $30.1 million in 2017. From 2013 to 2016, Medicare expenditures on Zetia decreased from $0.89 billion to $0.70 billion, whereas Medicaid Zetia expenditures decreased from $38.6 million in 2013 to $25.4 million in 2017. In 2017, PCSK9 inhibitors accounted for $317.3 million and $14.2 million in Medicare and Medicaid expenditures, respectively. Overall Medicare and Medicaid expenditures on lipid-lowering therapies decreased by $2.5 billion from 2013 to 2017.


[Costs of illness in dementia from a societal perspective. An overview].
Dementias are one of the most expensive disease groups among the population aged 65 years and over. This is mainly due to the patients' deficits in activities of daily living which increase with the progression of dementia, leading to an increasing need for care. As a result, the costs of dementia may more than double over the course of the disease. The costs of medical care account for a relatively small share of total costs and are not greatly influenced by disease severity. By contrast, the costs of care make up at least three quarters of total costs in the majority of studies. When patients are cared for in the community, most of the care is often provided informally by relatives. Accordingly, up to 75 or 80% of the costs of illness in this setting, from a societal perspective, may be due to informal care. Additional professional home care accounts for a relatively small share of total costs. The costs of caring for patients who live in the community are directly related to the degree of functional impairment. By contrast, it can be difficult to estimate the costs which are specifically due to dementia in patients that are institutionalised.


Selective synthesis of a [3]rotaxane consisting of size-complementary components and its stepwise deslippage.
An α-cyclodextrin-based size-complementary [3]rotaxane with an alkylene axle was selectively synthesized in one pot via an end-capping reaction with 2-bromophenyl isocyanate in water. Thermal degradation of the [3]rotaxane product yielded not only the original components but also the [2]rotaxane. Thermodynamic studies suggested a stepwise deslippage process.


Defect morphology, bone thickness, exposure settings and examiner experience affect the diagnostic accuracy of standardized digital periapical radiographic images but not of cone beam computed tomography in the detection of peri-implant osseous defects: An in vitro study.
To investigate the effect of defect morphology, bone thickness and examiner experience on the accuracy to detect the presence, the type and the depth of peri-implant defects with digital periapical radiographs (PAs) and cone beam computed tomography (CBCT) in an in vitro model. Thirty six implants were placed in fresh porcine rib bone with different types of standardized defects while sites with no defect served as control. Fourteen masked examiners evaluated 324 PAs and 108 CBCT images. The presence and type of defect, the location of the bottom of the defect and the location of first bone-to-implant contact were recorded. The sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each type of defect using actual measurements as the gold standard. The diagnostic accuracy for PAs was affected by defect morphology, exposure time, thickness of bone walls and the level of experience of the examiner. The overall diagnostic accuracy of CBCT was high (>96%) for all types of defects. Cone beam computed tomography showed better diagnostic accuracy in the detection of peri-implant defects, this can be attributed to the fact that CBCT seems to be less affected by variables that contribute to the poorer performance of PAs.


Earlier Morning Arrival to Pollen-Rewarding Flowers May Enable Feral Bumble Bees to Successfully Compete with Local Bee Species and Expand Their Distribution Range in a Mediterranean Habitat.
During recent decades, bumble bees (Bombus terrestris) have continuously expanded their range in the Mediterranean climate regions of Israel. To assess their potential effects on local bee communities, we monitored their diurnal and seasonal activity patterns, as well as those of native bee species in the Judean Hills. We found that all bee species tend to visit pollen-providing flowers at earlier times compared to nectar-providing flowers. Bumble bees and honey bees start foraging at earlier times and colder temperatures compared to other species of bees. This means that the two species of commercially managed social bees are potentially depleting much of the pollen, which is typically non-replenished, before most local species arrive to gather it. Taking into consideration the long activity season of bumble bees in the Judean hills, their ability to forage at the low temperatures of the early morning, and their capacity to collect pollen at early hours in the dry Mediterranean climate, feral and range-expanding bumble bees potentially pose a significant competitive pressure on native bee fauna. Their effects on local bees can further modify pollination networks, and lead to changes in the local flora.


Accuracy of echocardiographically estimated pulmonary artery pressure in dogs with myxomatous mitral valve disease.
Echocardiographically identified pulmonary hypertension is an independent predictor of poor outcome in dogs affected by myxomatous valvular degeneration (MMVD). Systolic pulmonary arterial pressure is routinely estimated based on its relationship with the Doppler-determined velocity of tricuspid regurgitation as defined by the simplified Bernoulli equation (sPAP_D). Experimental studies suggest that the method is imperfect, but its accuracy in dogs with MMVD is not known. Twenty dogs affected by MMVD that had cardiac remodeling and measurable tricuspid regurgitation. A flow-directed thermodilution monitoring catheter was percutaneously placed in the right external jugular vein and advanced to the main pulmonary artery. Pulmonary arterial systolic pressure was recorded (systolic pulmonary arterial pressure obtained by right heart catheterization [sPAP_C]). A second operator contemporaneously acquired tricuspid regurgitant velocity spectra to calculate sPAP_D. Each operator was blinded to the result of the other techniques. Technical difficulties prevented the analysis of catheterization data in two dogs. Eighteen measurement pairs were therefore used for comparison of sPAP_C and sPAP_D through correlation and Bland-Altman analysis. A statistically significant bias between sPAP_C and sPAP_D (mean difference = 0.5 mmHg; confidence interval = -6.5 mmHg, +7.5 mmHg) was not detected. The interval of agreement between the techniques was wide (-27.3 mmHg, +28.2 mmHg). A significant linear association between the two techniques was not identified (r = 0.11, p=0.17). Echocardiographically estimated pulmonary artery pressure poorly agrees with sPAP_C measurement in dogs affected by MMVD and cardiac remodeling with or without previously diagnosed congestive heart failure. In these dogs, sPAP_D could under- or over-estimate sPAP_C by more than 20 mmHg, and therefore caution should be used when interpreting sPAP_D.


The use of a multi-method approach to identify the pigments in the 12th century manuscript Liber Floridus.
A selection of illuminations of the 12th century manuscript Liber Floridus was analysed with Raman spectroscopy (in situ and laboratory measurements), X-ray fluorescence spectroscopy, UV-fluorescence photography and infrared reflectography (IRR). The aim of this study is to determine the pigments used, in order to search for anachronisms. Using a combination of Raman spectroscopy (molecular information) and X-ray fluorescence spectroscopy (elemental information) following pigments could be identified: ultramarine (Na(8-10)Al(6)Si(6)O(24)S(2-4)), azurite (2CuCO(3)·Cu(OH)(2)), caput mortuum (Fe(2)O(3)), vermilion (HgS), orpiment (As(2)S(3)) and lead white (2PbCO(3)·Pb(OH)(2)). Moreover, two synthetic red pigments, PR4 and PR176, and a degradation product, gypsum (CaSO(4)·2H(2)O), were present in the manuscript. To establish the origin of the modern materials UV-fluorescence photography was used. Infrared reflectography (IRR) was applied to visualise the underdrawing of the investigated folios.


Unintentional Medication Discrepancies at Admission Among Elderly Inpatients with Chronic Medical Conditions in Vietnam: A Single-Centre Observational Study.
Elderly patients are at high risk of unintentional medication discrepancies during transition of care as they are more likely to have multiple comorbidities and chronic diseases that require multiple medications. The aim of the study was to assess the frequency of unintentional medication discrepancies and identify the associated risk factors and potential clinical impact of them in elderly inpatients during hospital admission. A prospective observational study was conducted from July to December 2018 in an 800-bed geriatric hospital in Hanoi, North Vietnam. Patients over 60 years of age, admitted to one of selected internal medicine wards, taking at least one chronic medication before admission, and staying at least 48 h were eligible for enrollment. Medication discrepancies of chronic medications before and after admission of each participant were identified by a pharmacist using a step-by-step protocol for the medication reconciliation process. The identified discrepancies were then classified as intentional or unintentional by an assessment group comprising a pharmacist and a physician. A logistic regression model was used to identify risk factors of medication discrepancies. Among 192 enrolled patients, 328 medication discrepancies were identified, with 87 (26.5%) identified as unintentional. Nearly a third of enrolled patients (32.3%) had at least one unintentional medication discrepancy. The most common unintentional medication discrepancy was omission of drugs (75.9% of 87 medication discrepancies). The logistic regression analysis revealed a positive association between the number of discrepancies at admission and the type of treatment wards. Medication discrepancies are common at admission among Vietnamese elderly inpatients. This study highlights the importance of obtaining a comprehensive medication history at hospital admission and supports implementing a medication reconciliation program to reduce the negative impact of medication discrepancy, especially for the elderly population.


Unexpected role of electronic coupling between host redox centers in transport kinetics of lithium ions in olivine phosphate materials.
The discrepancy between the trend in the diffusion coefficient of a lithium ion (D Li+ ) and that in the activation energy of ion hopping signals hidden factors determining ion transport kinetics in layered olivine phosphate materials (LiMPO4). Combining density functional theory (DFT) calculations and the Landau-Zener electron transfer theory, we unravel this hidden factor to be the electronic coupling between redox centers of the host materials. The ion transport process in LiMPO4 is newly described as an ion-coupled electron transfer (ET) reaction, where the electronic coupling effect on D Li+ is considered by incorporating the electronic transmission coefficient into the rate constant of the transfer reaction. The new model and DFT calculation results rationalize experimental values of D Li+ for various LiMPO4 (M = Fe, Mn, Co, Ni) materials, which cannot be understood solely by the calculated activation barrier of ion hopping. Interestingly, the electronic coupling between host redox centers is found to play an essential role. Particularly, the sluggish ion mobility in LiFePO4 is due to a very weak electronic coupling. The obtained insights imply that one can improve the rate performance of intercalation materials for metal-ion batteries through modifying the electronic coupling between redox centers of host materials.


Occupational attainment as a function of abilities and interests: a longitudinal analysis using project TALENT data.
Ability, interest, gender, and family socioeconomic status of 13,248 tenth-grade participants in Project TALENT were studied as they relate to occupational attainment by using discriminant analysis. Individuals were classified into 12 broad categories reported 11 years after graduation. Accuracy analyses indicated correct classifications significantly above chance for all except the Technical and Sales categories. Within-category classification percentages were higher for all groups except Construction. Five canonical discriminant functions that jointly accounted for 96.8% of the between-groups variance were interpreted. The first 2 accounted for 81.9% of the variance. Function 1 was a general ability function; Function 2 differentiated the categories on the basis of mathematics ability and gender. Functions 3 through 5 accounted for 14.9% of the between-groups variance. Some implications of these findings are discussed.


A data-driven method for syndrome type identification and classification in traditional Chinese medicine.
The efficacy of traditional Chinese medicine (TCM) treatments for Western medicine (WM) diseases relies heavily on the proper classification of patients into TCM syndrome types. The authors developed a data-driven method for solving the classification problem, where syndrome types were identified and quantified based on statistical patterns detected in unlabeled symptom survey data. The new method is a generalization of latent class analysis (LCA), which has been widely applied in WM research to solve a similar problem, i.e., to identify subtypes of a patient population in the absence of a gold standard. A well-known weakness of LCA is that it makes an unrealistically strong independence assumption. The authors relaxed the assumption by first detecting symptom co-occurrence patterns from survey data and used those statistical patterns instead of the symptoms as features for LCA. This new method consists of six steps: data collection, symptom co-occurrence pattern discovery, statistical pattern interpretation, syndrome identification, syndrome type identification and syndrome type classification. A software package called Lantern has been developed to support the application of the method. The method was illustrated using a data set on vascular mild cognitive impairment.


Universal screening for thyroid disease during pregnancy should be performed.
Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening - the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.


Design, Synthesis, and Docking Studies of Thioimidazolyl Diketoacid Derivatives Targeting HIV-1 Integrase.
Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. This study aimed at developing a novel series of thioimidazolyl diketoacid derivatives characterizing various substituents at N-1 and 2-thio positions of the central ring as HIV-1integrase inhibitors. In this study, eighteen novel thioimidazolyl DKA derivatives were synthesized in a fivestep parallel procedure and tested in vitro for the inhibition of both IN ST reaction and the singlecycle HIV-1 replication in HeLa cell culture. The obtained molecules were evaluated using the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 mM. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. The most potent compound was found to be 18i with EC50 = 19 μM, IC50 = 0.9 μM, and SI = 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1integrase inhibitor.


Prelimbic cortex is a common brain area activated during cue-induced reinstatement of cocaine and heroin seeking in a polydrug self-administration rat model.
Many preclinical studies examined cue-induced relapse to heroin and cocaine seeking in animal models, but most of these studies examined only one drug at a time. In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self-administration relapse model in rats to determine similarities and differences in brain areas activated during cue-induced reinstatement of heroin and cocaine seeking. We trained rats to lever press for cocaine (1.0 mg/kg per infusion, 3-hr/day, 18 day) or heroin (0.03 mg/kg per infusion) on alternating days (9 day for each drug); drug infusions were paired with either intermittent or continuous light cue. Next, the rats underwent extinction training followed by tests for cue-induced reinstatement where they were exposed to either heroin- or cocaine-associated cues. We observed cue-selective reinstatement of drug seeking: the heroin cue selectively reinstated heroin seeking and the cocaine cue selectively reinstated cocaine seeking. We used Fos immunohistochemistry to assess cue-induced neuronal activation in different subregions of the medial prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala. Fos expression results indicated that only the prelimbic cortex (PL) was activated by both heroin and cocaine cues; in contrast, no significant cue-induced neuronal activation was observed in other brain areas. RNA in situ hybridization indicated that the proportion of glutamatergic and GABAergic markers in PL Fos-expressing cells was similar for the heroin and cocaine cue-activated neurons. Overall, the results indicate that PL may be a common brain area involved in both heroin and cocaine seeking during polydrug use.


Metformin reduces neuroinflammation and improves cognitive functions after traumatic brain injury.
Within the brain, traumatic brain injury (TBI) alters synaptic plasticity and increases neuroinflammation and neuronal death. Yet, there lacks effective TBI treatments providing pleiotropic beneficial effects on these diverse cellular processes necessary for functional recovery. Here, we show the diabetes drug, metformin, significantly improves cognitive functions after controlled cortical impact (CCI) injury in mice, showing improved spatial learning and nest building. Furthermore, injured animals treated with metformin exhibit increased ramification of microglia processes, indicating reduced neuroinflammation. Finally, metformin treatment in vitro increased neuronal activation of partitioning defective 1 (Par1), a family of Ser/Thr kinases playing a key role in synaptic plasticity and neuroinflammation. These results suggest metformin is a promising therapeutic agent for targeting multiple cellular processes necessary for functional TBI recovery.


Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis.
Eotaxin-1 (CCL11) induces the migration of different leukocyte types by interacting with CCR3. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are pathogenic effectors and a major CCR3-expressing cell. The aim of this study was to investigate the expression and function of CCL11 in RA FLS. The expression of CCL11 and CCR3 was evaluated by ELISA, immunofluorescence and quantitative PCR analysis. The CCL11 levels in serum and synovial fluids (SFs) from RA patients were significantly higher than those in serum from healthy controls and SFs from osteoarthritis patients. CCL11 and CCR3 were expressed in the RA synovial tissue lining layers. The secretion of CCL11 in RA FLS-conditioned medium and the mRNA expression of CCL11 and CCR3 were induced by TNF-α. Furthermore, CCL11 induced the mRNA expression of CCL11 and CCR3. Application of a CCR3 antagonist reduced TNF-α-induced CCL11 secretion from RA FLS. CCL11 induced the migration of RA FLS and monocytes. RA FLS migration was decreased by treatment with CCL11 siRNA. The migration of monocytes to medium conditioned with CCL11 siRNA-transfected and TNF-α-stimulated RA FLS was reduced. These data indicate that the self-amplification of CCL11 via CCR3 may play an important role in cell migration in RA.


Genetic monitoring on the world's first MSC eco-labeled common octopus (O. vulgaris) fishery in western Asturias, Spain.
Octopus vulgaris (Cuvier, 1797) is a cephalopod species with great economic value. In western Asturias (northwest of Spain), O. vulgaris artisanal fisheries are relatively well monitored and conditionally eco-labeled by the Marine Stewardship Council (MSC). Despite this, the Asturian octopus stocks have not been genetically assessed so far. In order to improve the current fishery plan and contrast the octopus eco-label validity in Asturias, 539 individuals from five regions of the O. vulgaris geographic distribution, including temporal samplings in Asturias, were collected and genotyped at thirteen microsatellite loci. All the samples under analysis were in agreement with Hardy-Weinberg expectations. Spatial levels of genetic differentiation were estimated using F-statistics, multidimensional scaling, and Bayesian analyses. Results suggested that the O. vulgaris consists of at least four genetically different stocks coming from two ancestral lineages. In addition, temporal analyses showed stability in terms of genetic variation and high NE (> 50) for several generations in different localities within Asturias, pointing out to indeed sustainable fishery exploitation levels. Even though, the current Asturias fishery plan shows no significant genetic damages to the stocks, the regional-specific management plans need systematic genetic monitoring schemes as part of an efficient and preventive regional fishery regulation strategy.


Lymph node metastasis in head and neck squamous carcinoma: Efficacy of intravoxel incoherent motion magnetic resonance imaging for the differential diagnosis.
To evaluate the value of pure molecular diffusion(D), perfusion-related diffusion (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) based on intravoxel incoherent motion (IVIM) theory for differential diagnosis of metastatic lymph nodes (LNs) in head and neck squamous cell carcinoma(HNSCC). 29 patients with HNSCC and 20 patients with lymph node hyperplasia (LNH) were enrolled in this retrospective study, underwent magnetic resonance (MR) examination. IVIM Diffusion-weighted imaging (IVIM-DWI) was performed with 13 b values. D, D*, f and ADC values were compared between two groups. The diagnostic value of ADC, D, D* and D·D* value were evaluated by Receiver operating characteristic (ROC) curve. Two radiologists measured D, D*, f and ADC values independently. 33 malignant LNs in HNSCC group and 22 benign LNs in LNH group (minimum diameter, ≥5mm) were successfully examined, ADC(P<0.05), D (P<0.01) and f (P<0.01) were significantly lower in malignant LNs than that in benign LNs, whereas D* was significantly higher (P<0.01). The area under the ROC curve (AUC) for D·D* was 0.983 and was larger than that for D* (0.952), D (0.78) and ADC (0.67). Our results indicate that IVIM DWI is feasible in the diagnosis of LN metastasis. D was significantly decreased in malignant LNs reflected increased nuclear-to-cytoplasmic ratio tissue, and D* was significantly increased reflected increased blood vessel generation and parenchymal perfusion in malignant LNs.


Managing behavioural and developmental paediatric conditions in rural outpatient clinics: An insight to the challenge ahead.
The aim of this study is to characterise the nature and caseload of general paediatric outpatient clinics in rural Queensland and to compare the findings with national data. A retrospective clinical audit of medical records in paediatric clinics at two rural hospitals was undertaken over a 6-month period. Data extracted included demographics, diagnostic category and onward referral outcomes. The same diagnostic categories were used as the national Children Attending Paediatricians Study (CAPS) to facilitate comparison. A total of 346 records were reviewed, 56 (16.2%) documented Aboriginal and Torres Strait Islander descent. Compared to national data, significantly more children with behavioural/developmental diagnoses were seen in the rural clinics (CAPS 33.8%; rural 59.2%; P < 0.001). In contrast, children presenting with medical conditions (CAPS 48.2%; rural 28.6%; P < 0.001) and mixed medical/developmental conditions (CAPS 17.9%; rural 12.1%; P = 0.006) were seen less frequently in the rural clinics. Referral rates from the rural sites were lower than the rates reported by CAPS for children with behavioural/developmental diagnoses (CAPS 35.9%, rural 24.9%; P = 0.002) and mixed diagnoses (CAPS 40.6%, rural 19.0%; P = 0.005), while there was no difference in referral rates for children with medical diagnoses (CAPS 16.1%, rural 18.2%; P = 0.575). Rural paediatricians' caseloads are dominated by developmental/behavioural conditions, however children with these conditions are less likely to be referred to allied health and psychology services. The reasons for lower referral rates and specific pressures upon rural health services need to be investigated in future studies to provide better health services for rural children.


Return to work and productivity loss after surgery: A health economic evaluation.
We aimed to identify preoperative psychosocial factors associated with return-to-work (RTW) and the associated cost of productivity loss due to work absenteeism following surgery. Research demonstrates a high economic burden from productivity loss after surgery, but the comparative cost of productivity loss relative to income across different operations has not been examined. A mixed surgical cohort recruited for a randomized controlled trial were prospectively followed for up to two years following surgery with daily phone assessments to three months, weekly assessments thereafter to six months, then monthly assessments thereafter to determine RTW status, opioid use and pain. 183 of 207 (88.3%) patients in paid employment prior to surgery, who provided at least one day of follow-up, were included in this analysis. The average cost of productivity loss due to work absenteeism was $13 761 (median $9064). Patients who underwent total knee replacement incurred the highest income loss. Medical claims filed before surgery were significantly associated with relative income loss (AOR 5.09; 95% CI 1.73-14.96; p < 0.01) and delayed postoperative RTW. Elevated preoperative PTSD symptoms were associated with delayed RTW (HR 0.78; 95%CI 0.63-0.96; p-value = 0.02) while male gender (HR 1.63; 95%CI 1.11-2.38; p-value = 0.01) was associated with faster postoperative RTW. Surgery places a high economic burden on individuals due to postoperative productivity loss. Multidisciplinary approaches, such as pathways, that facilitate the operation and recovery may mitigate the economic consequences for patients, employers, and the healthcare system.


[Endometritis--a diagnostic problem. Differentialdiagnostical considerations including histological and microbiological methods (author's transl)].
In 100 patients with the assumed diagnosis "endometritis" an examination program including histological and microbiological methods was conducted. In only 73% of these, the histological examination confirmed the assumed diagnosis, and only in 3% concerning the microbiological tests; therefore other diagnoses such as peritoneal irritation at ovulation, adenomyosis uteri and spastic pelviopathias were dominant. The diagnosis of an endometritis therefore is often an exclusive one and should induce subtle examination methods before an unspecific antibiotic therapy is begun. This procedure is absolutely possible regarding out-patients.


Comparative analysis of cardiomyocyte differentiation from human embryonic stem cells under 3-D and 2-D culture conditions.
Post-myocardial infarction cardiomyocytes are the most important target cell types for cardiac repair. Many of the applications envisaged for human embryonic stem cells (hESC)-derived cardiomyocytes demand that the differentiation procedure be robust, cost effective and high yielding. Various lines of evidence including our earlier study suggest that hESCs have distinct preferences to become heart cells. However, a direct comparison between different protocols has not yet been reported to date. Here, we performed a logical and systematic comparison of cardiomyocytes obtained from hESCs via embryoid bodies (EBs) in suspension versus adherent static cultures of feeder-free hES colonies representing three-dimensional (3-D) and two-dimensional (2-D) culture systems, respectively. An in-depth characterization of the beating cells revealed appropriate cardiac marker expression both at gene and protein levels. Despite using similar media, 3-D and 2-D cultures showed significant variation in growth and ability to form beating areas. While the expression of pre-cardiac mesoderm markers like GATA-4, HAND1, Myf5, Msx1, and BMP-IIR remained unaltered; levels of functional heart-specific markers such as MLC-2A/2V, cTnT, ANP, Phospholamban, α-MHC and KV4.3 were substantially up-regulated in 3-D compared to 2-D cultures. Concurrently we observed a sharp decline in the expression of ESC, ectoderm and endoderm markers including Oct-4, Sox-2, NFH, Sox-1, Sox-17 and AFP. Further immunocytochemistry and flow cytometry demonstrated a higher percentage of cells positive for Brachyury, desmin and cardiac troponin in 3-D cultures. Our results underscore the higher efficiency of cardiomyocytes derived via 3-D cultures. This finding enriches our basic understanding of the differentiation pattern in hESC-derived cardiomyocytes.


Influence of fruit-based beverages on efficacy of Lacticaseibacillus rhamnosus GG (Lactobacillus rhamnosus GG) against DSS-induced intestinal inflammation.
Different lines of evidences from clinical, epidemiological and biochemical studies have established that optimal nutrition including probiotic and fruit phenolics can mitigate the risk and morbidity associated with some chronic diseases. The basis for this observation is the potential synergies that may exist between probiotic strains and different bioactive components of food matrices. This study was conceptualized to compare the efficiency of a probiotic strain in two different fruit matrices. Two fruits, viz., sea buckthorn (Hippophae rhamnoides) (SBT) and apples (Malus pumila) (APJ) were chosen and the anti-inflammatory effects of L. rhamnosus GG (ATCC 53103) (LR) fortified in SBT and APJ were analysed against dextran sulphate sodium (DSS) induced colitis in zebrafish (Danio rerio). The results showed that administration of probiotic (LR) fortified, malt supplemented SBT beverage (SBT + M + LR) had better restorative potential on the intestinal barrier function and mucosal damage, in comparison to LR fortified, malt supplemented APJ beverage (APJ + M + LR). SBT + M + LR demonstrated adequate anti-oxidant potential by enhancing the CAT, SOD, GPx and GSH activities, impaired due to DSS administration. The increase in the expressions of toll like receptor (TLR)-2, TLR-4 and TLR-5 induced by DSS were significantly inhibited by SBT + M + LR administration. Gene expression of pro-inflammatory markers, (NF-κB, TNF-α, IL-1β, IL-6, IL-8, CCL20, MPO and MMP9) were attenuated by SBT + M + LR treatment in intestinal tissues of DSS-treated zebrafishes. Notably, SBT + M + LR increased the expression of anti-inflammatory cytokine, IL-10. The study provides evidence that specific interactions between fruit matrix and probiotic strain can provide adjunct therapeutic strategy to manage intestinal inflammation.


Effect of Delayed Cord Clamping on Hematocrit, and Thermal and Hemodynamic Stability in Preterm Neonates: A Randomized Controlled Trial.
To evaluate the short term clinical effects of delayed cord clamping in preterm neonates. Randomized controlled trial. A tertiary care neonatal unit from October 2013 to September 2014. 78 mothers with preterm labor between 27 to 316/7 weeks gestation. Early cord clamping (10 s), delayed cord clamping (60 s) or delayed cord clamping (60 s) along with intramuscular ergometrine (500 µg) administered to the mother. Primary: hematocrit at 4 h after birth; Secondary: temperature on admission in neonatal intensive care unit, blood pressure (non-invasive) at 12 h, and urinary output for initial 72 h. Mean (SD) hematocrit at 4 h of birth was 58.9 (2.4)% in delayed cord clamping group, and 58.7 (2.1) % in delayed cord clamping with ergometrine group as compared to 47.6 (1.3) % in early cord clamping group. Mean (SD) temperature on admission in NICU was 35.8 (0.2)ºC, 35.8 (0.3)ºC, and 35.5 (0.3)ºC, respectively in these three groups. The mean (SD) non-invasive blood pressure at 12 h of birth was 45.8 (7.0) mmHg, 45.8 (9.0) mmHg, and 35.5 (8.6) mmHg, respectively in these three groups. Mean (SD) urinary output on day 1 of life was 1.1 (0.2) mL/kg/h, 1.1 (0.2) mL/kg/hr and 0.9 (0.2) ml/kg/h, respectively. In preterm neonates delayed cord clamping along with lowering the infant below perineum or incision site and administration of ergometrine to mother has significant benefits in terms of increase in hematocrit, higher temperature on admission, and higher blood pressure and urinary output during perinatal transition.


Immune, Blood Cell, and Blood Gas Biomarkers of Delirium in Elderly Individuals with Hip Fracture Surgery.
Postoperative delirium in elderly people with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. The aim of this study was to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers. In this prospective study, we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit, Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete blood count and venous blood gas markers were obtained at the same time points. Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process.


Infantile chronic peripheral neuropathy with giant axons. Report of a case.
An 8-year-old boy with a slowly progressive motor neuropathy is described. The first signs appeared at the age of 3 years. Histological examination of the sural nerve showed the presence of numerous segmental axonal swellings and features of demyelination as well as remyelination. These enlargements were filled with irregularly orientated 10 nm filaments. The case resembled the previously described cases of giant axonal neuropathy but differed from them in absence of kinky hair.


Adenylyl cyclase-cAMP system inhibits thrombin-induced HSP27 in vascular smooth muscle cells.
We previously reported that thrombin stimulates the induction of heat shock protein (HSP) 27 via p38 mitogen-activated protein (MAP) kinase activation in aortic smooth muscle A10 cells. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on the thrombin-stimulated induction of HSP27 in A10 cells. Forskolin, a direct activator of adenylyl cyclase, reduced the thrombin-induced p38 MAP kinase phosphorylation, and significantly suppressed the thrombin-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the HSP27 accumulation. Furthermore, dibutyryl-cAMP (DBcAMP), a permeable analog of cAMP, significantly suppressed the accumulation of HSP27. On the other hand, calphostin C, an inhibitor of protein kinase C (PKC), reduced the thrombin-induced p38 MAP kinase phosphorylation, and significantly suppressed the thrombin-stimulated accumulation of HSP27. Moreover, forskolin reduced the p38 MAP kinase phosphorylation induced by the 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC-activating phorbol ester, and significantly suppressed the TPA-stimulated accumulation of HSP27. These results indicate that adenylyl cyclase-cAMP system has an inhibitory role in thrombin-stimulated HSP27 induction in aortic smooth muscle cells, and the effect seems to be exerted on the thrombin-induced PKC- p38 MAP kinase signaling pathway.


Assessing environmental fate of hexavalent chromium as influenced by fractionation of ferrihydrite with dissolved organic matter.
The dynamic interactions among iron (Fe) oxides, dissolved organic matter (DOM) and toxic trace metals play crucial roles in risk assessment and environmental remediation. Although the inhibitory effects of DOM on the iron oxides transformation process have been studied previously, there is still a lack of mechanistic and quantitative understanding on the kinetics of Cr(VI) and ferrihydrite transformation in the present of DOM. In this study, we investigated the fractionation process of DOM on ferrihydrite and its influence on the fate of Cr(VI) and transformation of ferrihydrite. The result of three-dimension excitation emission matrix (3D-EEM), Q-Exactive LC-MS/MS, X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HR-TEM) indicated that fulvic acid-like compounds of DOM were the mainly fractionated compounds on the surface of ferrihydrite, which further inhibited the transformation of ferrihydrite. Besides, bracewellite (CrO(OH)) generated as an accompanied mineral during the transformation of ferrihydrite in the present of Cr(VI). Based on the DFT theoretical calculation, we concluded that Cr(VI) mainly in the form of HCr O4- was more inclined to be adsorbed on iron-oxide tetrahedron by inner-sphere monodentate mononuclear configurations. The findings on the dynamic coupling among Fe oxide transformation and Cr(VI) sequestration under the effect of DOM provided the basis for accurately predicting the fate of trace elements and iron mineral.


Indium Tribromide-Catalysed Transfer-Hydrogenation: Expanding the Scope of the Hydrogenation and of the Regiodivergent DH or HD Addition to Alkenes.
The transfer-hydrogenation as well as the regioselective and regiodivergent addition of H-D from regiospecific deuterated dihydroaromatic compounds to a variety of 1,1-di- and trisubstituted alkenes was realised with InBr3 in dichloro(m)ethane. In comparison with the previously reported BF3 ⋅Et2 O-catalysed process, electron-deficient aryl-substituents can be applied reliably and thereby several restrictions could be lifted, and new types of substrates could be transformed successfully in hydrodeuterogenation as well as deuterohydrogenation transfer-hydrogenation reactions.


Serial Genotyping of the Human Papillomavirus in Cervical Cancer: An Insight Into Virome Dynamics During Chemoradiation Therapy.
Human papillomavirus (HPV) is the primary driver of cervical cancer. Although studies in other malignancies correlated peripheral blood DNA clearance with favorable outcomes, research on the prognostic value of HPV clearance in gynecologic cancers using intratumoral HPV is scarce. We aimed to quantify the intratumoral HPV virome in patients undergoing chemoradiation therapy (CRT) and associate this with clinical characteristics and outcomes. This prospective study enrolled 79 patients with stage IB-IVB cervical cancer undergoing definitive CRT. Cervical tumor swabs collected at baseline and week 5 (end of intensity modulated radiation therapy) were sent for shotgun metagenome sequencing and processed via VirMAP, a viral genome sequencing and identification tool for all known HPV types. The data were categorized into HPV groups (16, 18, high risk [HR], and low risk [LR]). We used independent t tests and Wilcoxon signed-rank to compare continuous variables and χ2 and Fisher exact tests to compare categorical variables. Kaplan-Meier survival modeling was performed with log-rank testing. HPV genotyping was verified using quantitative polymerase chain reaction to validate VirMAP results using receiver operating characteristic curve and Cohen's kappa. At baseline, 42%, 12%, 25%, and 16% of patients were positive for HPV 16, HPV 18, HPV HR, and HPV LR, respectively, and 8% were HPV negative. HPV type was associated with insurance status and CRT response. Patients with HPV 16+ and other HPV HR+ tumors were significantly more likely to have a complete response to CRT versus patients with HPV 18 and HPV LR/HPV-negative tumors. Overall HPV viral loads predominantly decreased throughout CRT, except for HPV LR viral load. Rarer, less well-studied HPV types in cervical tumors are clinically significant. HPV 18 and HPV LR/negative tumors are associated with poor CRT response. This feasibility study provides a framework for a larger study of intratumoral HPV profiling to predict outcomes in patients with cervical cancer.


Corrigendum: Mass spectrometry metabolomics and feature-based molecular networking reveals population-specific chemistry in some species of the Sceletium genus.
[This corrects the article DOI: 10.3389/fnut.2022.819753.].


Protein Partitioning into Ordered Membrane Domains: Insights from Simulations.
Cellular membranes are laterally organized into domains of distinct structures and compositions by the differential interaction affinities between various membrane lipids and proteins. A prominent example of such structures are lipid rafts, which are ordered, tightly packed domains that have been widely implicated in cellular processes. The functionality of raft domains is driven by their selective recruitment of specific membrane proteins to regulate their interactions and functions; however, there have been few general insights into the factors that determine the partitioning of membrane proteins between coexisting liquid domains. In this work, we used extensive coarse-grained and atomistic molecular dynamics simulations, potential of mean force calculations, and conceptual models to describe the partitioning dynamics and energetics of a model transmembrane domain from the linker of activation of T cells. We find that partitioning between domains is determined by an interplay between protein-lipid interactions and differential lipid packing between raft and nonraft domains. Specifically, we show that partitioning into ordered domains is promoted by preferential interactions between peptides and ordered lipids, mediated in large part by modification of the peptides by saturated fatty acids (i.e., palmitoylation). Ordered phase affinity is also promoted by elastic effects, specifically hydrophobic matching between the membrane and the peptide. Conversely, ordered domain partitioning is disfavored by the tight molecular packing of the lipids therein. The balance of these dominant drivers determines partitioning. In the case of the wild-type linker of activation of T cells transmembrane domain, these factors combine to yield enrichment of the peptide at Lo/Ld interfaces. These results define some of the general principles governing protein partitioning between coexisting membrane domains and potentially explain previous disparities among experiments and simulations across model systems.


Wait-and-See Policy for a Small Pancreatic Schwannoma Diagnosed With Endoscopic Ultrasound With Fine-Needle Aspiration.
Pancreatic schwannomas are very rare tumors, usually diagnosed incidentally after surgery. In literature, only 17 patients underwent endoscopic ultrasound (EUS) with fine-needle aspiration and diagnosis was reached only in 9 subjects. We report the case of a woman in whom a computed tomography revealed a mass in the uncinate process of the pancreas. EUS-fine-needle aspiration demonstrated a 1.3 × 1.1 cm hypoechoic lesion, cytology revealed sheets of spindle cells, and immunocytochemistry led to the diagnosis of schwannoma. Relying on EUS features and on the low proliferation index, a follow-up program was set. Four years later, the patient is asymptomatic and the mass is unchanged.


Strategic Synthesis of 'Picket Fence' Porphyrins Based on Nonplanar Macrocycles.
Traditional 'picket fence' porphyrin systems have been a topic of interest for their capacity to direct steric shielding effects selectively to one side of the macrocycle. Sterically overcrowded porphyrin systems that adopt macrocycle deformations have recently drawn attention for their applications in organocatalysis and sensing. Here we explore the combined benefits of nonplanar porphyrins and the old molecular design to bring new concepts to the playing field. The challenging ortho-positions of meso-phenyl residues in dodecasubstituted porphyrin systems led us to transition to less hindered para- and meta-sites and develop selective demethylation based on the steric interplay. Isolation of the symmetrical target compound [2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(3,5-dipivaloyloxyphenyl)porphyrin] was investigated under two synthetic pathways. The obtained insight was used to isolate unsymmetrical [2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(2-nitro-5-pivaloyloxyphenyl)porphyrin]. Upon separation of the atropisomers, a detailed single-crystal X-ray crystallographic analysis highlighted intrinsic intermolecular interactions. The nonplanarity of these systems in combination with 'picket fence' motifs provides an important feature in the design of supramolecular ensembles.


Patients' Perspective About the Cost of Diabetes Management: An Analysis of Online Health Communities.
To understand the perspectives of persons' living with diabetes about the increasing cost of diabetes management through an analysis of online health communities (OHCs) and the impact of persons' participation in OHCs on their capacity and treatment burden. A qualitative study of 556 blog posts submitted between January 1, 2007 and December 31, 2017 to 4 diabetes social networking sites was conducted between March 2018 and July 2019. All posts were coded inductively using thematic analysis procedures. Eton's Burden of Treatment Framework and Boehmer's Theory of Patient Capacity directed triangulation of themes with existing theory. Three themes were identified: (1) cost barriers to care: participants describe individual and systemic cost barriers that inhibit prescribed therapy goals; (2) impact of financial cost on health: participants describe the financial effects of care on their physical and emotional health; and (3) saving strategies to overcome cost impact: participants discuss practical strategies that help them achieve therapy goals. Finally, we also identify that the use of OHCs serves to increase persons' capacity with the potential to decrease treatment burden, ultimately improving mental and physical health. High cost for diabetes care generated barriers that negatively affected physical health and emotional states. Participant-shared experiences in OHCs increased participants' capacity to manage the burden. Potential solutions include cost-based shared decision-making tools and advocacy for policy change.


Biodistribution of model 105Rh-labeled tetradentate thiamacrocycles in rats.
105Rh(III)Cl2 complexes with a limited series of [14]ane- and [16]ane- thia macrocycles were prepared and their biodistributions in Sprague-Dawley rats studied. These studies demonstrate that modifications in the structure and composition of the 105Rh-thia macrocycle complexes produce significant differences in their uptake and retention in both the liver and kidneys. The results indicate that the cis-Rh(III)Cl2-[14]ane thiamacrocycles exhibit less kidney retention than the corresponding trans-Rh(III)Cl2-[16]ane thiamacrocycles. In addition, the presence of a side chain containing a carboxylate group will produce decreased retention of activity in the kidneys. HPLC analysis of urine from these animals indicates no observable in vivo metabolism or dissociation of these chelates in the blood stream.


Plasma levels of troponin T after electrical cardioversion of atrial fibrillation and flutter.
To establish possible myocardial damage by direct-current countershock, we measured plasma levels of troponin T after electrical cardioversion in 33 nonselected patients with atrial fibrillation or flutter. Unchanged normal levels of troponin T indicate that significant myocardial cell injury by shocks in the usual dosage is unlikely to occur.


Children's Financial Dependence on Mothers: Propensity and Duration.
Over 40 percent of American children rely primarily on their mothers' earnings for financial support in cross-sectional surveys. Yet these data understate mothers' role as their family's primary earner. Using longitudinal Survey of Income and Program Participation panels beginning in 2014, we create multistate life table estimates of mothers' duration as primary earner as well as single-decrement life table estimates of their chance of ever being the primary earner over the first 18 years of motherhood. Using a threshold of 60 percent of household earnings to determine primary earning status, mothers average 4.19 years as their families' primary earner in the 18 years following first birth. Mothers with some college but no degree spent the most years as primary earners, about 5.09 years on average, as did mothers with nonmarital first births, about 5.69 years. Around 70 percent of American mothers can reasonably expect to be their household's primary earner at some point during their first 18 years of motherhood.


Long-term in vivo assessment of bioengineered skin substitutes: a clinical study.
The aim of the study was an objective in vivo assessment of skin properties after reconstruction with two artificial dermal substitutes, Integra® and Hyalomatrix®. Twenty-seven patients underwent reconstruction of 36 skin-loss sites with full-thickness skin graft, split-thickness skin graft, Hyalomatrix® bioengineered skin substitute and sequential split-thickness skin graft and Integra® bioengineered skin substitute and sequential split-thickness skin graft. Objective assessments were carried out using three instrumental devices: Multi Probe Adapter System MPA; 22 MHz ultrasound skin scan; and Primos Pico for a three-dimensional (3D) skin scan. The skin parameters under study in our sample were: corneometry, transepidermal water loss, elastometry, colorimetry, skin thickness and 3D skin surface pattern. A skin reconstruction with Hyalomatrix seemed to most closely approach the hydration, transepidermal water loss and skin surface 3D pattern of normal skin. A skin reconstruction with Integra seemed to demonstrate the best skin colour feature and elastic properties. Although no statistically significant differences were observed, the descriptive analysis of the outcomes might suggest a better cell regulation, regenerated extracellular matrix and neoangiogenesis with the use of Hyalomatrix, and the formation of a more elastic regenerated dermis, with overall better physical, mechanical and optical properties, with the use of Integra.


Insights into β-amyloid transition prevention by cucurbit[7]uril from molecular modeling.
In this study, comparable molecular dynamic (MD) simulations of 1.2 microseconds were performed to clarify the prevention of the β-amyloid peptide (Aβ1-42) aggregation by cucurbit[7]uril (CB[7]). The accumulation of this peptide in the brain is one of the most harmful in Alzheimer's disease. The inhibition mechanism of Aβ1-42 aggregation by different molecules is attributed to preventing of Aβ1-42 conformational transition from α-helix to the β-sheet structure. However, our structural analysis shows that the pure water and aqueous solution of the CB[7] denature the native Aβ1-42 α-helix structure forming different compactness and unfolded conformations, not in β-sheet form. On the other hand, in the three CB[7]@Aβ1-42 complexes, it was observed the encapsulation of N-terminal (Asp1), Lys16, and Val36 by CB[7] along the MD trajectory, and not with aromatic residues as suggested by the literature. Only in one CB[7]@Aβ1-42 complex was observed stable Asp23-Lys28 salt bridge with an average distance of 0.36 nm. All CB[7]@Aβ1-42 complexes are very stable with binding free energy lowest than ∼-50 kcal/mol between the CB[7] and Aβ1-42 monomer from MM/PBSA calculation. Therefore, herein we show that the mechanism of the prevention of elongation protofibril by CB[7] is due to the disruption of the Asp23-Lys28 salt bridge and steric effects of CB[7]@Aβ1-42 complex with the fibril lattice, and not due to the transition from α-helix to β-sheet following the dock-lock mechanism.Communicated by Ramaswamy H. Sarma.


UROPA: a tool for Universal RObust Peak Annotation.
The annotation of genomic ranges of interest represents a recurring task for bioinformatics analyses. These ranges can originate from various sources, including peaks called for transcription factor binding sites (TFBS) or histone modification ChIP-seq experiments, chromatin structure and accessibility experiments (such as ATAC-seq), but also from other types of predictions that result in genomic ranges. While peak annotation primarily driven by ChiP-seq was extensively explored, many approaches remain simplistic ("most closely located TSS"), rely on fixed pre-built references, or require complex scripting tasks on behalf of the user. An adaptable, fast, and universal tool, capable to annotate genomic ranges in the respective biological context is critically missing. UROPA (Universal RObust Peak Annotator) is a command line based tool, intended for universal genomic range annotation. Based on a configuration file, different target features can be prioritized with multiple integrated queries. These can be sensitive for feature type, distance, strand specificity, feature attributes (e.g. protein_coding) or anchor position relative to the feature. UROPA can incorporate reference annotation files (GTF) from different sources (Gencode, Ensembl, RefSeq), as well as custom reference annotation files. Statistics and plots transparently summarize the annotation process. UROPA is implemented in Python and R.


Body rocking, head banging, and head rolling in normal children.
Body rocking, head banging, and head rolling--three rhythmic behaviors that involve stimulation of the vestibular system--were studies in 525 normal children. Data analyses focused on two issues: (1) the prevalence and duration of these habits and their relationship to child and family factors and (2) the hypothesis that children who persistently displayed such behaviors would be reported as developmentally more advanced than "non-self-stimulators." Body rocking was the earliest to appear and most prevalent of the three habits. Head banging and head rolling had roughly the same prevalence and age of onset. Comparisons of "self-stimulators" with "non-self-stimulators" yielded no significant effects for birth order or SES; only for head banging was a significant (3:1) ratio of males to females found. A comparison of the ages at which 12 "milestones" first appeared supported the hypothesis of developmental precocity for the body rockers and the head bangers, but not for the head rollers.


Pathogenesis, diagnosis and treatment of diabetic ketoacidosis.
The diagnosis of diabetic ketoacidosis must be suspected and the initiation of treatment should be prompt to provide a satisfactory outcome in the treatment of diabetic ketoacidosis. Corrections of fluid and electrolyte deficiencies should be made slowly; rapid "push"injections or large infusions of sodium bicarbonate should avoided and ample amounts of potassium should be given early. Precautions should be taken so that blood glucose concentrations do not fall rapidly, and so that blood glucose levels of 250-300 mg/100 ml are maintained by the administration of 5-10% glucose solutions. Bicarbonate therapy is indicated only in severe acidosis (pH less than or equal to 7.1). Physicians who are trained in the care of diabetes mellitus should supervise the treatment. In our hospital the same staff physicians and fellows attend all patients with diabetes. In addition the efforts of our house staff and nurses have contributed significantly to the care of these patients.


Some aspects of non-precious metal alloys for ceramic restorations.
Comment is made regarding the cost, related to working properties, of non-precious metal alloys compared to precious metal alloys for ceramics and their possible potential for the production of allergic response.


Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety.
Rats were chronically treated with chlordiazepoxide (CDP 10 mg/kg/day) or vehicle for 27 days. Twenty-four hours after their last dose, they received flumazenil (4 mg/kg) or vehicle and were tested in the social interaction test, in a low-light, familiar arena. CDP withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. This was completely reversed by flumazenil. A second group received CDP for 27 days and, in addition, received a single dose of flumazenil (4 mg/kg) 6 days before testing. Flumazenil prevented the development of the anxiogenic withdrawal response in these rats.


Bio-conjugation of anti-human CD3 monoclonal antibodies to magnetic nanoparticles by using cyanogen bromide: A potential for cell sorting and noninvasive diagnosis.
The conjugation of monoclonal antibodies with superparamagnetic iron oxide nanoparticles (SPIONs) has appeared as a potential multifunctional clinical tool, which can effectively diagnose cancers and monitor their treatment, specifically. Despite the presence of different methods for conjugating antibodies to iron oxide nanoparticles, novel cost-effective and simpler conjugation techniques should be performed in this regard. In current study, an anti-CD3 monoclonal antibody was conjugated to the Fe3O4 coated by carboxymethyl dextran (CMD) using cyanogen bromide (CNBr). Moreover, EDC/NHS techniques were applied as a positive control. The experimental results showed that the Conjugation was performed and the presence of the antibody conjugated to the MNPs in human xenograft tumors was confirmed using Prussian blue (PB) staining, following magnetic resonance imaging (MRI), 30 min after injection. This conjugation method was shown to be able to separate CD3+ T lymphocytes efficiently from whole blood with high purity. Accordingly, this type of bio-conjugation method can be utilized in the future for cell sorting, and can be applied for adopted cell therapies such as CAR-T cell (Chimeric antigen receptor T cell) therapy, as well as targeted MRI imaging.


Anterior Supine Intermuscular Total Hip Arthroplasty at an Ambulatory Surgery Center Versus Hospitalization: Cost and Adverse Events.
This study compares anterior supine intermuscular total hip arthroplasty performed at an ambulatory surgery center with the same procedure performed in a hospital setting in regard to complications and costs. The ambulatory surgery center had significantly shorter postoperative stays and superior visual analog pain scores at 3 months. No differences were noted in operative time, blood loss, or complications. Costs were significantly different between groups, with significant cost savings noted in the ambulatory surgery center group.