Risk assessment and avoidance in juvenile golden hamsters exposed to repeated stress.
Juvenile hamsters are typically less vulnerable to social subjugation than adults, although they will avoid aggressive individuals in some situations. The purpose of this study was to determine the extent to which social subjugation stimulates fear- or anxiety-like behavior in juvenile hamsters in both social and non-social contexts. Social context testing was conducted in a Y-maze while the non-social context apparatus consisted of an open field arena and a lat-maze. In the Y-maze, subjects were exposed to an unfamiliar aggressive adult hamster. Compared with non-subjugated controls, subjugated juveniles spent significantly more time in the area furthest from the aggressive adult stimulus. In addition, socially stressed animals were more likely to avoid the arm of the maze containing the social stimulus. When they did walk in the arm containing the social stimulus, subjugated individuals were more likely to ambulate slowly. Subjugated hamsters also performed fewer olfactory investigations in the proximity of the unfamiliar aggressive individual. Despite these behavioral differences detected between groups during testing in a social context, we observed no differences between groups in the open field and lat-maze. This suggests that the effects of subjugation observed in the Y-maze are specific to exposure to a social context and that social subjugation in juvenile hamsters does not result in a generalized state of fear. Instead, subjugated juveniles learned to avoid adult males and were otherwise behaviorally similar to non-subjugated controls.


Differences in ventilatory responses to hypoxia and hypercapnia between normal and judo athletes with moderate obesity.
Hypercapnic and hypoxic ventilatory sensitivities were compared in twenty-one judoists and 24 control subjects with similar degrees of moderate obesity. Data from ten non-obese control subjects were also included as a reference. Mean body weight (BW) and % of ideal body weight in the judoists and the obese and non-obese controls were 100 +/- 14.8, 94.4 +/- 5.3 and 63.4 +/- 6.1 (mean +/- SD) kg, and 142.3 +/- 16.7, 142.2 +/- 12.9 and 98.4 +/- 10.7%, respectively. Mean body fat in the judoists was 16.2 +/- 13.9%, being 25.3 +/- 7.7% in the obese control group, the difference being significant (p less than 0.01). Hypercapnic sensitivities in terms of the CO2 ventilatory response slope (S) and its normalized value for 70 kg BW (SN) of the obese controls were higher than the judoists. These findings were also verified by the CO2-occlusion pressure responses. S and SN in the obese controls were significantly correlated with BW and % body fat. However, no positive correlation was found between BW and S or SN in the judoists as well as between lean body mass and S or SN in the obese control. Hypoxic sensitivity in terms of the PETO2-ventilation hyperbola slope (A) and its normalized value (AN) in the obese control was significantly higher than the non-obese control, but the difference from the judoists was not significant. A and AN were found to increase with increasing % body fat in both judoists and obese controls.(ABSTRACT TRUNCATED AT 250 WORDS)


Qualitative and Artificial Intelligence-Based Sentiment Analysis of Turkish Twitter Messages Related to Autism Spectrum Disorders.
The aim of our study was to conduct an emotional analysis of Turkish Twitter messages related to autism spectrum disorders (ASD). An emotion analysis was performed using quantitative and qualitative analysis methods on Turkish Twitter messages shared between November 2021 and January 2022 that contained the words "autism" and "autistic." It was found that 81.5% of the 13,042 messages that constituted the sample of this study contained neutral emotions. The most frequently used words in Twitter messages were autism, a, universe, strong, patience, warriors, and happy. The qualitative analysis revealed three main themes. These themes were: "experiences," "informing society and awareness," and "humiliation." In this study, it was found that Turkish Twitter messages related to autism, which were analyzed using artificial intelligence-based emotion analysis, often contained neutral emotions. While the content of these messages, often shared by parents, was related to experiences, and the messages shared by pediatric psychiatrists and rehabilitation center employees were informative in nature, it was determined that the word "autism" was used to insult, which is outside of its medical meaning.


Growth trajectories during infancy have a significant impact on body composition in childhood.
Evidence supports that growth trajectory during infancy has a major impact on body composition. We aimed to examine body composition in children born small for gestational age (SGA) or appropriate for gestational age (AGA) adjusted for postnatal growth velocity. We enrolled 365 children, 75 SGA and 290 AGA, aged 7 to 10 years, examining anthropometrics, skinfold thickness, and body composition using bioelectrical impedance analysis. Growth velocity was defined as rapid or slow (weight gain > or <0.67 z-scores, respectively). Gestational age, sex, delivery mode, gestational diabetes, hypertension, nutrition, exercise, parental body mass index (BMI), and socioeconomic status were considered. At a mean of 9 years of age, SGA compared with AGA-born children, had significantly lower lean mass. BMI was negatively associated with SGA status (beta = 0.80, P = .046), after adjusting for birth weight, delivery mode, and breastfeeding. The lean mass index was negatively associated with SGA status (beta = 0.39, P = .018), after adjusting for the same factors. SGA-born participants with slow growth velocity had significantly lower lean mass in comparison to AGA-born counterparts. SGA-born children with rapid compared with those with slow growth velocity had significantly higher absolute fat mass. BMI was negatively associated with a slow postnatal growth pattern (beta = 0.59, P = .023), and the lean mass index was negatively associated with a slow postnatal growth pattern (beta = 0.78, P = .006), after adjusting for the same factors. In conclusion, SGA-born children presented a lower lean mass in comparison to AGA-born counterparts, whereas BMI and lean mass index were negatively associated with slow postnatal growth velocity.


Rapid and sensitive detection of miRNA via light scatter-aided emulsion-based isothermal amplification using a custom low-cost device.
MicroRNAs are likely to be a next-generation clinical biomarker for many diseases. While gold-standard technologies, e.g., reverse transcription-quantitative polymerase chain reaction (RT-qPCR), exist for microRNA detection, there is a need for rapid and low-cost testing. Here, an emulsion loop-mediated isothermal amplification (eLAMP) assay was developed for miRNA that compartmentalizes a LAMP reaction and shortens the time-to-detection. The miRNA was a primer to facilitate the overall amplification rate of template DNA. Light scatter intensity decreased when the emulsion droplet got smaller during the ongoing amplification, which was utilized to moitor the amplification non-invasively. A custom low-cost device was designed and fabricated using a computer cooling fan, a Peltier heater, an LED, a photoresistor, and a temperature controller. It allowed more stable vortexing and accurate light scatter detection. Three miRNAs, miR-21, miR-16, and miR-192, were successfully detected using the custom device. Specifically, new template and primer sequences were developed for miR-16 and miR-192. Zeta potential measurements and microscopic observations confirmed emulsion size reduction and amplicon adsorption. The detection limit was 0.01 fM, corresponding to 2.4 copies per reaction, and the detection could be made in 5 min. Since the assays were rapid and both template and miRNA + template could eventually be amplified, we introduced the success rate (compared to the 95% confidence interval of the template result) as a new measure, which worked well with lower concentrations and inefficient amplifications. This assay brings us one step closer to allowing circulating miRNA biomarker detection to become commonplace in the clinical world.


The action of noradrenaline on single smooth muscle cells freshly dispersed from the guinea-pig pulmonary artery.
Responses to ionophoretically-applied noradrenaline were investigated with micro-electrodes in whole tissue preparations and with patch pipettes in isolated cells dispersed from the guinea-pig pulmonary artery. In whole tissue and dispersed cells noradrenaline evoked monophasic depolarizations which had a similar time course. In dispersed cells the amplitude of electronic potentials was reduced during the noradrenaline-evoked depolarization. Under voltage clamp noradrenaline elicited an inward current, which persisted in 18 mM external potassium with the membrane potential set at the potassium equilibrium potential. In voltage clamp experiments the amplitude of current steps to hyperpolarizing voltage jumps was increased during the noradrenaline-induced inward current. These data suggest that the depolarization to noradrenaline in the guinea-pig pulmonary artery is mediated by an increase in membrane conductance.


Aminoglutethimide treatment in advanced breast cancer: an efficient therapy as a late endocrine alternative in a sequential therapeutic approach.
During the last 2 years we have treated 24 patients (23 females and 1 male) with aminoglutethimide plus glucocorticoid for advanced breast cancer. More than half of the patients had received more than 3 systemic treatments before start of aminoglutethimide (AG), and at least half of the patients had been given more than 2 different endocrine regimens. There were 8 previous responders to endocrine therapy and in 10 patients steroid receptor status predicted response to therapy. Nine of 22 patients (two had to stop after less than 1 month due to acute toxicity) had an objective response; there were 2 complete responders. Most side effects were not serious, subsiding within a few weeks. In one patient agranulocytosis was observed. AG with glucocorticoid replacement seems to be an effective treatment as a late endocrine alternative in a sequence of different endocrine regimens.


Development of monoclonal antibodies and immunochromatographic lateral flow device for rapid test of alanine aminotransferase isoenzyme 1.
Alanine aminotransferase (ALT) has been used as a sensitive marker for liver injury in people and in preclinical toxicity studies. But measurement of ALT isoenzymes, ALT1 and ALT2, was reported to be of more diagnostic value. The aim of this study is to develop an ideal pair of anti-ALT1 monoclonal antibodies (MAbs) of high specificity and affinity, and subsequently prepare a Immunochromatographic lateral flow device (LFD) for rapid test of ALT1 in human serums. The complete coding sequence of ALT1 gene (1500 bp) was cloned from human hepatoma G2 cells (HepG2) and inserted into the expression vector pET-32a(+). ALT1 recombinant protein was routinely prepared by E. coli BL21 (DE3) expression and Ni(2+) affinity purification. Balb/c mice were immunized with purified ALT1 and the splenocytes were fused with Sp2/0 myeloma cells. The positive clones, verified by indirect enzyme-linked immunosorbent assay (ELISA) using purified ALT1, were subcloned to single clones by limiting dilution process. A MAb pair was selected from the obtained MAbs according the sandwich ELISA pairing results and then used for lateral flow device (LFD) production. After evaluation of the sensitivity and specificity, the LFD strips were employed to test human serum samples with known ALT activity levels. ALT1 recombinant protein was expectedly prepared by expression and purification. A total of 8 stable clones that produced antibodies specifically recognizing ALT1 protein were developed. After sandwich ELISA pairing, an ideal pair of anti-ALT1 MAbs, designated as BD7 and DG3, were selected and proved to be of high specificity, titer and affinity. Based on the MAb pair, LFD strips specifically for ALT1 rapid test were subsequently prepared. The detection threshold of the LFD strips was 12 U/L. No cross reaction was found. The ALT1 LFD with high sensitivity and specificity was successfully developed. It is valuable for testing ALT1 protein in human sera and can be a beneficial complement for traditional ALT test.


A new algorithm for fetal heart rate detection: Fractional order calculus approach.
A new modified Pan-Tompkins' (mPT) method for fetal heart rate detection is presented. The mPT method is based on the hypothesis that optimal fractional order derivative and optimal window width of the moving average filter would enable efficient estimation of fetal heart rate from surface abdominal electrophysiological recordings with relatively low signal-to-noise ratios. The algorithm is tested on signals recorded from the abdomen of pregnant women available from the PhysioNet Computing in Cardiology Challenge database. Fetal heart rate detection is performed on 10-s long segments selected by the estimation of signal-to-noise ratios (the extravagance of the fetal QRS peak to its surroundings and to the whole signal; and the mean ratio of fetal and maternal QRS peaks) and on the manually selected segments. The best results are obtained via criteria based on the extravagance of the fetal QRS peak to its surroundings that reached average sensitivity of 97%, positive predictive value of 97%, error rate of ∼3.5%, and F1 score of 97%. The obtained averaged optimal parameters for mPT are 0.51 for fractional order and 24.5 ms for the window width of the moving average filter. Proposed mPT algorithm showed satisfactory performance for fetal heart rate detection. Further adaptations of the presented mPT method could be used for peak detection in noisy environments in biomedical signal analysis in general.


Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation.
Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.


Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad.
The micro/macrovascular complications of diabetes cause considerable morbidity and premature mortality. The SGLT2 inhibitors are the first diabetes medications with significant benefits on microvascular disease (nephropathy) and macrovascular cardiovascular disease. In this review, we evaluate one of the potential mechanisms for these cardiorenal benefits-the production of ketones, their benefits, and risks. In recent cardiovascular outcome trials (CVOTs), the SGLT2 inhibitors demonstrated significant cardiorenal benefits and they are now approved to reduce CV events/death, heart failure hospitalization, and progression to end-stage renal disease. Glucosuria induced by the SGLT2 inhibitors leads to increased ketone production. Ketones are an efficient fuel source and can improve myocardial and renal function. Further, the ketone body beta-hydroxybutyrate exhibits anti-inflammatory/anti-oxidative actions, which favorably impact myocardial and renal remodeling/fibrosis. Uncontrolled ketogenesis leads to ketoacidosis, especially during conditions of acute illness and excessive insulin dose reductions. The SGLT2 inhibitors have demonstrated significant cardiorenal benefits in large CVOTs. Studies are in progress to elucidate whether SGLT2 inhibitor-induced low-grade hyperketonemia contributes to these benefits.


Impact of elective neck dissection on the outcome of oral squamous cell carcinomas arising in the maxillary alveolus and hard palate.
Whether elective lymph neck dissection (ELND) is associated with improved survival in oral squamous cell carcinomas (SCC) of the maxillary alveolus/hard palate is not known. One hundred ninety-nine patients presenting de novo and receiving treatment for clinically node negative SCC of the maxillary alveolus/hard palate at 2 cancer centers between 1985 and 2011 were analyzed. Forty-two patients (21%) received ELND. Occult nodal metastases were present in 29% of the dissected necks. The ELND group had more T3 to T4 status tumors (62% vs 34%; p < .001) and positive-margin resections (59% vs 38%; p = .019). Patients undergoing ELND experienced lower rates of neck recurrence (6% vs 21%; p = .031), superior 5-year recurrence-free survival (68% vs 45%; p = .026), and overall survival (86% vs 62%; p = .043). ELND was associated with a 2-fold decrease in risk of recurrence in multivariable analysis. ELND was associated with lower rates of recurrence and improved survival in SCC of the maxillary alveolus/hard palate. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1688-E1694, 2016.


Dietary Supplementation with Agave tequilana (Weber Var. Blue) Stem Powder Improves the Performance and Intestinal Integrity of Broiler Rabbits.
This study evaluated the effect of Agave tequilana (Weber var. azul) stem powder on the growth performance and the intestinal integrity in rabbits. A total of 120 male rabbits [New Zealand × California] were weaned for 35 days and randomized into four dietary treatments, 15 replicates per treatment, and two rabbits per replicate. The treatments consisted of a basal diet (T0) and dietary supplementation with 0.5% (T1), 1.0% (T2) and 1.5% (T3) of Agave tequilana stem powder. The T3 treatment improved the body weight and average daily gain (p < 0.05) compared to the other groups, without affecting viability and feed conversion ratio (p > 0.05). Furthermore, the T3 treatment enhanced (p < 0.05) the thickness of the muscular and mucous layers, and the height, thickness, and number of villi in the duodenum (p < 0.05). However, this treatment (T3) significantly decreased (p < 0.05) values for the area and depth of the crypts in the duodenum and the villus/crypt ratio. Likewise, in the cecum, T3 treatment provoked a marked decrease (p < 0.05) in the depth and thickness of the crypts. The results indicate that the dietary use with 1.5% of A. tequilana stem powder had a natural growth-promoting effect and enhanced the histomorphometry of the concentric layers (muscle and mucosa), villi, and crypts as indicators of intestinal health in rabbits.


Single chain-urokinase binds to oxidized fibrin(ogen) derivatives.
Single chain- urokinase (scu-PA), in contrast to two chain urokinase, is a physiological plasminogen activator of fibrin selectivity. The mechanism of selective fibrinolysis of scu- PA has not been clarified up to now. This study has shown that fibrin selectivity might involve oxidative processes. Binding studies with immobilized oxidized fibrinogen degradation products (FDP) demonstrated higher affinity of scu-PA to oxidized than to unmodified FDP. The fibrin(ogen) domain responsible for this oxidant mediated increase of scu-PA affinity is localized in the D-subunit of fibrin(ogen). Thus, experimental data upon the interaction of scu-PA with fibrin(ogen) using oxidized and I- labelled fibrin(ogen) might be interpreted with caution: the oxidized product may behave in a distinct manner than the unoxidized, native, one. Activated leukocytes release large amounts of scu-PA and of oxidants of the chloramine type. The oxidants could contribute significantly to fibrinolysis and proteolysis in areas of inflammation, preparing fibrin for its specific degradation. The present data support the concept of an involvement of oxidative processes in the fibrinolytic pathway.


Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome.
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it has been suggested that additional mutations lead to progression of MDS to AML, the causative agent(s) for such mutations remains unclear. Oxidative stress is a potential cause, therefore, we evaluated levels of reactive oxygen species (ROS) in NUP98-HOXD13 (NHD13) transgenic mice, a murine model for MDS. Increased levels of ROS were detected in bone marrow nucleated cells (BMNC) that express CD71, a marker for cell proliferation, as well as immature, lineage negative bone marrow nucleated cells from NHD13 mice. In addition to the increase in ROS, increased DNA double strand breaks and activation of a G2/M phase cell cycle checkpoint were noted in NHD13 BMNC. Finally, using an in vivo assay for mutation frequency, we detected an increased mutation frequency in NHD13 BMNC. These results suggest that oxidative stress may contribute to disease progression of MDS to AML through ineffective repair of DNA damage and acquisition of oncogenic mutations.


Individual differences in T1w/T2w ratio development during childhood.
Myelination is a key developmental process that promotes rapid and efficient information transfer. Myelin also stabilizes existing brain networks and thus may constrain neuroplasticity, defined here as the brain's potential to change in response to experiences rather than the canonical definition as the process of change. Characterizing individual differences in neuroplasticity may shed light on mechanisms by which early experiences shape learning, brain and body development, and response to interventions. The T1-weighted/T2-weighted (T1w/T2w) MRI signal ratio is a proxy measure of cortical microstructure and thus neuroplasticity. Here, in pre-registered analyses, we investigated individual differences in T1w/T2w ratios in children (ages 4-10, n = 157). T1w/T2w ratios were positively associated with age within early-developing sensorimotor and attention regions. We also tested whether socioeconomic status, cognition (crystallized knowledge or fluid reasoning), and biological age (as measured with molar eruption) were related to T1w/T2w signal but found no significant effects. Associations among T1w/T2w ratios, early experiences, and cognition may emerge later in adolescence and may not be strong enough to detect in moderate sample sizes.


Structures, Mechanisms, and Functions of His-Me Finger Nucleases.
His-Me finger (also called HNH or ββα-me) nucleases, are a large superfamily of nucleases that share limited sequence homology, but all members carry a highly similar catalytic motif exhibiting a ββα topology. This review represents a structural comparison of His-Me finger nucleases, summarizing their substrate-binding and recognition strategies, mechanisms of enzymatic hydrolysis, cellular functions, and the various means of activity regulation. His-Me finger nucleases usually function as monomers, making a single nick in nucleic acids to degrade foreign or host genomes, or as homodimers that introduce double-stranded DNA breaks for DNA restriction, integration, recombination, and repair. Various cellular neutralizing machineries have evolved to regulate the activity of His-Me finger nucleases, thereby maintaining genome integrity and cellular functionality.


Nonsense-mediated mRNA decay in neuronal physiology and neurodegeneration.
The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation of these processes serves to safeguard the spatiotemporal fidelity of gene expression. Nonsense-mediated mRNA decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates gene expression in a wide range of scenarios in the nervous system, including neurodevelopment, learning, and memory formation. Moreover, NMD dysregulation has been implicated in a broad range of neurodevelopmental and neurodegenerative disorders. We discuss how NMD and related aspects of mRNA translation regulate key neuronal functions and, in particular, we focus on evidence implicating these processes in the molecular pathogenesis of neurodegeneration. Finally, we discuss the therapeutic potential and challenges of targeting mRNA translation and NMD across the spectrum of largely untreatable neurological diseases.


Exploring efficacy of natural-derived acetylphenol scaffold inhibitors for α-glucosidase: Synthesis, in vitro and in vivo biochemical studies.
The discovery of novel α-glucosidase inhibitors and anti-diabetic candidates from natural or natural-derived products represents an attractive therapeutic option. Here, a collection of acetylphenol analogues derived from paeonol and acetophenone were synthesized and evaluated for their α-glucosidase inhibitory activity. Most of derivatives, such as 9a-9e, 9i, 9m-9n and 11d-1e, (IC50 = 0.57 ± 0.01 μM to 8.45 ± 0.57 μM), exhibited higher inhibitory activity than the parent natural products and were by far more potent than the antidiabetic drug acarbose (IC50 = 57.01 ± 0.03 μM). Among these, 9e and 11d showed the most potent activity in a non-competitive manner. The binding processes between the two most potent compounds and α-glucosidase were spontaneous. Hydrophobic interactions were the main forces for the formation and stabilization of the enzyme - acetylphenol scaffold inhibitor complex, and induced the topography image changes and aggregation of α-glucosidase. In addition, everted intestinal sleeves in vitro and the maltose loading test in vivo further demonstrated the α-glucosidase inhibition of the two compounds, and our findings proved that they have significant postprandial hypoglycemic effects.


Parsing surrounding space into regions.
Surrounding space is not inherently organized, but we tend to treat it as though it consisted of regions (e.g., front, back, right, and left). The current studies show that these conceptual regions have characteristics that reflect our typical interactions with space. Three experiments examined the relative sizes and resolutions of front, back, left, and right around oneself. Front, argued to be the most important horizontal region, was found to be (a) largest, (b) recalled with the greatest precision, and (c) described with the greatest degree pf detao. Our findings suggest that some of the characteristics of the category model proposed by Huttenlocher, Hedges, and Duncan (1991) regarding memory for pictured circular displays may be generalized to space around oneself. More broadly, our results support and extend the spatial framework analysis of representation of surrounding space (Franklin & Tversky, 1990).


Comparative field water relations of four co-occurring chaparral shrub species.
The seasonal course of water relations was measured in the field in Adenostoma fasciculatum, Quercus dumosa, Ceanothus greggii, and Arctostaphylos glauca, four prominent members of the southern California chaparral vegetation. Ceanothus greggii and A. glauca developed similar seasonal patterns of minimum leaf water potentials, as estimated by xylem pressure measurements, which were much less negative than A. fasciculatum and Q. dumosa growing in close proximity on the same pole-facing slope site. Adenostoma fasciculatum on an adjacent equator-facing slope developed more negative water potentials than did A. fasciculatum on the pole-facing slope.Leaf conductance differed between species, and by leaf age class and slope exposure within a species. The greatest differences were measured between leaf age classes in A. fasciculatum on the pole-facing slope, with new leaves showing the greatest conductances early in the season. The same trend was measured in A. fasciculatum on the equator-facing slope, but the differences were less between leaf age classes and diminished earlier in the season than in A. fasciculatum on the pole-facing slope. The analysis of daily hysteresis in the leaf conductance-water potential relation suggests that early in the season when water is available, stomatal behavior is simultaneously governed by a complex of environmental factors, while late in the season stomatal behavior becomes increasingly dominated by tissue water status.


Serological evidence of rift valley fever virus among acute febrile patients in Southern Mozambique during and after the 2013 heavy rainfall and flooding: implication for the management of febrile illness.
Rift Valley fever virus (RVFV) remains heavily neglected in humans in Mozambique, even though recent outbreaks were reported in neighboring countries in humans and several cases of RVFV in cattle were reported in several districts in Mozambique. We conducted a cross sectional study during and after severe flooding that occurred in 2013 in Mozambique. Paired acute and convalescent serum samples were tested from febrile patients attending a primary health care unit in a suburban area of Maputo city for the presence of IgG and IgM antibodies against Rift Valley fever virus (RVFV) using enzyme-linked immunosorbent assay (ELISA). Seroconversion of IgG anti-RVFV was observed in 5 % (10/200) of convalescent patients and specific IgM anti-RVFV was detected in one acute patient (0.5 %; 1/200). All sera from acute patient tested negative by real time PCR. In conclusion, our results suggest that RVF represent an important but neglected cause of febrile illness following periods of flooding in southern Mozambique.


Antigen-independent priming: a transitional response of bovine gammadelta T-cells to infection.
Analysis of global gene expression in immune cells has provided unique insights into immune system function and response to infection. Recently, we applied microarray and serial analysis of gene expression (SAGE) techniques to the study of gammadelta T-cell function in humans and cattle. The intent of this review is to summarize the knowledge gained since our original comprehensive studies of bovine gammadelta T-cell subsets. More recently, we have characterized the effects of mucosal infection or treatment with microbial products or mitogens on gene expression patterns in sorted gammadelta and alphabeta T-cells. These studies provided new insights into the function of bovine gammadelta T-cells and led to a model in which response to pathogen-associated molecular patterns (PAMPs) induces 'priming' of gammadelta T-cells, resulting in more robust responses to downstream cytokine and/or antigen signals. PAMP primed gammadelta T-cells are defined by up-regulation of a select number of cytokines, including MIP1alpha and MIP1beta, and by antigens such as surface IL2 receptor alpha (IL-2Ralpha) and CD69, in the absence of a prototypic marker for an activated gammadelta T-cell, IFN-gamma. Furthermore, PAMP primed gammadelta T-cells are more capable of proliferation in response to IL-2 or IL-15 in the absence of antigen. PAMPs such as endotoxin, peptidoglycan and beta-glucan are effective gammadelta T-cell priming agents, but the most potent antigen-independent priming agonists defined to date are condensed oligomeric tannins produced by some plants.


The Societal Influences and Quality of Life Among Healthcare Team Members During the COVID-19 Pandemic.
Background: The coronavirus infection disease 2019 (COVID-19) pandemic is likely to put healthcare professionals across the world in an unprecedented situation. Methods: A total of 683 healthcare workers were recruited in this study. Short form-12 items (SF-12), Societal Influences Survey Questionnaire (SISQ), and Disaster-Related Psychological Screening Test (DRPST) were used to survey participants. Multiple linear regression and structural equation model (SEM) were used to explore the possible factors to the societal influences and quality of life. Results: After multiple linear regression analysis, female, older, more education years, married, regular intake, and posttraumatic stress disorder (PTSD) frequency had positive association with SISQ. To physical component summary (PCS) of SF-12, chronic illness, sleep score, PTSD frequency, and social distance had negative association, and exercise habits had positive association. A mental component summary (MCS) value of SF-12, age, participate in social activities, and social information had positive association, and PTSD frequency, sleep score, social anxiety, and depression had negative association. Under SEM analysis, PTSD had positive influence on SISQ. Sleep score and MCS value had negative influences on SISQ. PTSD severity, older age, sleep score, smoking, and nursing staff had negative influences on PCS value. Young age, PTSD frequency, sleep score, and depression had negative influences on MCS value. Conclusion: Healthcare team members with severe PTSD symptoms suffered more societal influences. Relative to PTSD severity, PTSD frequency was more important to the quality of life. Members of older age who frequently participate in clubs, volunteers, or charity activities had better mental life quality.


Detection of signature volatiles for cariogenic microorganisms.
The development of a breath test by the identification of volatile organic compounds (VOCs) emitted by cariogenic bacteria is a promising approach for caries risk assessment and early caries detection. The aim of the present study was to investigate the volatile profiles of three major cariogenic bacteria and to assess whether the obtained signatures were species-specific. Therefore, the headspaces above cultures of Streptococcus mutans, Lactobacillus salivarius and Propionibacterium acidifaciens were analysed after 24 and 48 h of cultivation using gas chromatography and mass spectrometry. A volatile database was queried for the obtained VOC profiles. Sixty-four compounds were detected within the analysed culture headspaces and were absent (36) or at least only present in minor amounts (28) in the control headspace. For S. mutans 18, for L. salivarius three and for P. acidifaciens five compounds were found to be unique signature VOCs. Database matching revealed that the identified signatures of all bacteria were unique. Furthermore, 13 of the 64 detected substances have not been previously reported to be emitted by bacteria or fungi. Specific VOC signatures were found in all the investigated bacteria cultures. The obtained results encourage further research to investigate the transferability to in vivo conditions towards the development of a breath test.


Pirfenidone: in idiopathic pulmonary fibrosis.
Pirfenidone is an orally administered pyridine that has orphan designation for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in the EU. Pirfenidone 2403 mg/day for 72 weeks administered to patients with IPF was associated with a significantly lower mean decline in the percent predicted forced vital capacity than placebo (primary endpoint) according to data from one of two randomized, double-blind, multinational trials (studies 004 and 006 [also known as the CAPACITY trials]), and data from a pooled analysis of both trials. In another randomized, double-blind, multicentre Japanese trial, the adjusted mean in the change in vital capacity from baseline to week 52 was significantly lower in patients with IPF who received pirfenidone 1800 mg/day (considered to be comparable to the 2403 mg/day dose in studies 004 and 006 on a weight-normalized basis) than in those who received placebo (primary endpoint). Pirfenidone had an acceptable tolerability profile in clinical trials, with most adverse events being mild to moderate in severity.


Association between the hOGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis based on 22,475 subjects.
The Ser326Cys polymorphism in the human 8-oxogunaine glycosylase (hOGG1) gene with lung cancer susceptibility had been investigated, but results were inconsistent and underpowered. The aim of this study was to conduct a meta-analysis assessing the association of hOGG1 Ser326Cys polymorphism with risk of lung cancer. Relevant studies were identified through a search of MEDLINE, PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database (CBM) using terms "lung cancer", "hOGG1" or "OGG1", "polymorphism" or "variation" and the last search updated on May 1, 2013. In this meta-analysis, we assessed 30 published studies involving 22,475 subjects that investigated the association between the hOGG1 Ser326Cys polymorphism and lung cancer susceptibility. Overall, the hOGG1 Ser326Cys polymorphism was not associated with lung cancer susceptibility in different genetic models (dominant model comparison: OR = 0.133; 95% CI = 0.111-0.161; P(heterogeneity) = 0.000), and recessive model: OR = 0.543; 95% CI = 0.399-0.739; P(heterogeneity) = 0.000). Similarly, in the stratified analyses by ethnicity, significantly increased risks were found among Asians for homozygote comparison (OR = 0.850; 95% CI = 0.732 0.986; P(heterogeneity) = 0.064), and dominant model (OR = 0.160; 95% CI = 0.137-0.187; P(heterogeneity) = 0.001), and Caucasians for dominant model (OR = 1.35; 95% CI = 1.03-1.77; P(heterogeneity) = 0.015), and recessive model (OR = 1.35; 95% CI = 1.03-1.77; P(heterogeneity) = 0.015). In population-based populations, marginally significant increased risks were found in dominant model (OR = 0.143; 95% CI = 0.111 0.184; P(heterogeneity) = 0.000) and recessive model (OR = 0.429; 95% CI = 0.261-0.705; P(heterogeneity) = 0.000). We also found a significant difference between hOGG1 Ser326Cys genotype and lung cancer susceptibility in studies with hospital-based controls for homozygote model (OR = 0.798; 95% CI = 0.649-0.982; P(heterogeneity )= 0.007),dominant model (OR = 0.122; 95% CI = 0.091-0.163; P(heterogeneity) = 0.000). Our data showed that the hOGG1 Ser326Cys polymorphism contributed to the risk of lung cancer. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3842531131031605.


Alterations in Local Peri-Infarct Blood Gases in Stroke Patients Undergoing Thrombectomy.
Ischemic stroke is a prevalent, devastating disease with high morbidity and mortality. Despite extensive research using animal models, significant gaps remain in understanding the pathological processes in human stroke. We previously developed a tissue bank to analyze the blood immediately proximal and distal to an intracranial thrombus in patients undergoing mechanical thrombectomy (ClinicalTrials.gov identifier, NCT03153683). Our goal for the present project was to evaluate the blood gas changes and acid/base balance during stroke and determine how vascular collateralization affects these changes. We analyzed the blood samples and computed tomography angiography collateral scores from the first 62 patients in the BACTRAC (Blood and Clot Thrombectomy Registry and Collaboration) registry. The bicarbonate, partial pressure of oxygen, and partial pressure of carbon dioxide (pCO2) values of the intracranial (distal) and systemic (proximal) arterial blood relative to the occlusive thrombus were analyzed. Analysis of the group differences in systemic and intracranial blood gas values was also performed. The partial pressure of oxygen, pCO2, and bicarbonate levels were all significantly higher in the systemic blood than in the intracranial blood (P < 0.001 for all) at thrombectomy. Collateralization did not significantly affect the distal blood gas values. Compared with the female patients, the male patients had had higher systemic pCO2 values (39.8 vs. 36.6 mm Hg; P = 0.0065) and lower systemic and intracranial pH values (7.351 vs. 7.392; P = 0.0047). The arterial blood gases differed immediately proximal and distal to thrombi in large vessel occlusive stroke. Although vascular collateralization did not appear to affect the blood gas changes, some blood gas values differed between men and women. The changes in bicarbonate and pCO2 suggested a compensatory acid-base process occurring at the time of infarction.


Sex-dimorphic neuroestradiol regulation of ventromedial hypothalamic nucleus glucoregulatory transmitter and glycogen metabolism enzyme protein expression in the rat.
Ventromedial hypothalamic nucleus (VMN) gluco-regulatory transmission is subject to sex-specific control by estradiol. The VMN is characterized by high levels of aromatase expression. The aromatase inhibitor letrozole (LZ) was used with high-resolution microdissection/Western blot techniques to address the hypothesis that neuroestradiol exerts sex-dimorphic control of VMN neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD) protein expression. Glycogen metabolism impacts VMN nNOS and GAD profiles; here, LZ treatment effects on VMN glycogen synthase (GS) and phosphorylase brain- (GPbb; glucoprivic-sensitive) and muscle (GPmm; norepinephrine-sensitive) variant proteins were examined. VMN aromatase protein content was similar between sexes. Intracerebroventricular LZ infusion of testes-intact male and ovariectomized, estradiol-replaced female rats blocked insulin-induced hypoglycemic (IIH) up-regulation of this profile. LZ exerted sex-contingent effects on basal VMN nNOS and GAD expression, but blocked IIH-induced NO stimulation and GAD suppression in each sex. Sex-contingent LZ effects on basal and hypoglycemic patterns of GPbb and GPmm expression occurred at distinctive levels of the VMN. LZ correspondingly down- or up-regulated baseline pyruvate recycling pathway marker protein expression in males (glutaminase) and females (malic enzyme-1), and altered INS effects on those proteins. Results infer that neuroestradiol is required in each sex for optimal VMN metabolic transmitter signaling of hypoglycemic energy deficiency. Sex differences in VMN GP variant protein levels and sensitivity to aromatase may correlate with sex-dimorphic glycogen mobilization during this metabolic stress. Neuroestradiol may also exert sex-specific effects on glucogenic amino acid energy yield by actions on distinctive enzyme targets in each sex.


Micromotion measurement at the interfaces of cemented tibial endoprosthetic replacements: A new standardized in vitro model using open-cell rigid foam.
Early aseptic loosening following primary total knee arthroplasty related to several factors might appear at the interface implant-cement or cement-bone. A standardized in vitro model might provide information on the relevance of single variable parameter of cementation including technique and cement respectively bone structure on fixation strength. Micromotion measurement using different directions of load should detect the primary stability of the interfaces. An open-cell rigid foam model was used for cementation of PFC-Sigma tibial trays with Palacos®. Pins were applied to the model for continuous non-destructive measurement. Relative micromotions for rotation, valgus-varus and extension flexion stress were detected at the interfaces as well as cement penetration was measured. The reproducibility of the measurement could be shown for all interfaces in extension-flexion movements. For rotation a negative trend was shown for the interface cement-prosthesis and cement-bone concerning varus-valgus stress reflecting varying surgical cementation technique. More micromotion related to extension-flexion force might reflect the design of the implant. Measurement of relative micromotion and cement distribution appear accurate to detect small differences of movement at different interfaces of cemented tibial implants and the results are reproducible for most parameter. An increased number of specimens should achieve statistical relevance for all measurements.


Turkish version of the 5-item Compassion Measurement Tool: A validity and reliability study.
The aim of this methodological study with a cross-sectional design study was to examine the validity and reliability of the Turkish form of the 5-item Compassion Measurement Tool. The sample was 402 patients in a university hospital. The Content Validity Index was 0.96. Total item correlation values were between 0.559 and 0.685. Cronbach's alpha coefficient was 0.83. The scale could be used as five items, under a single factor as in the original version. A high correlation was found between patients' compassion perception and nursing care satisfaction scores. Turkish version of the 5-item Compassion Measurement Tool is a valid and reliable tool.


[Studies of childhood non-Hodgkin's lymphoma--treatment results with the CCLSG NHL 960 protocol. Children's Cancer and Leukemia Study Group (CCLSG)].
We report here on the preliminary treatment findings of a CCLSG NHL 960 study that was initiated in March 1996. In this study, 37 patients with non-Hodgkin's lymphoma were assigned to 4 different treatment groups according to disease stage and histology: (1) localized disease; (2) advanced disease, lymphoblastic type; (3) advanced disease, large cell type; and (4) advanced disease, Burkitt type. The first three groups received the modified protocols of the NHL 890 study. Groups 1 and 3 received COPADM induction therapy (CPM, VCR, PRD, ADR, and MTX). After achieving remission, Group 1 received only maintenance therapy consisting of alternate administration of 7 drugs, while Group 3 received additional intensification therapy with combination chemotherapy consisting of MTX and Ara-C, followed by a maintenance phase involving the administration of 9 drugs. Group 2 received COPADL induction therapy (CPM, VCR, PRD, ADR, and LASP) and consolidation/intensification therapies followed by a maintenance phase. Group 4 received short-term intensive COPADM polychemotherapy. Twelve patients with localized with localized disease (stage I-II) and 25 patients with advanced disease (stage III-IV) were enrolled in this study. Except for 2 patients in the advanced disease stages who died earlier in the course of the study, all patients remained in remission.


Selective polarographic determination of stannous ion in technetium radiopharmaceutical cold kits.
The aim of this work was to develop a selective method for quantification of Sn(II) and Sn(IV) in dimercaptosuccinic acid (DMSA), ethylcysteinate dimer (ECD), methylenediphosphonic acid (MDP), and pyrophosphate radiopharmaceutical cold kits by differential pulse polarography. A dripping mercury electrode 150 polarographic/stripping analyzer with a conventional 3-electrode configuration was used with 3 M H(2)SO(4) and 3 M HCl supporting electrolytes for Sn(II) and Sn(IV), respectively. The polarographic analysis was performed using a 1-s drop time, 50-mV·s(-1) scan rate, -50-mV pulse amplitude, 40-ms pulse time, and 10-mV step amplitude. To quantify Sn(IV), oxidation of Sn(II) by H(2)O(2) was performed. The calibration curves for Sn(II) and Sn(IV) were obtained in the range of 0-10 μg·mL(-1). The analytic curves for Sn(II) in 3 M H(2)SO(4) and Sn(IV) in 3 M HCl were represented by the following equations: i (μA) = 0.098 [Sn(II)] + 0.018 (r(2) = 0.998) and i (μA) = 0.092 [Sn(IV)] + 0.016 (r(2) = 0.998), respectively. The detection limits were 0.21 μg·mL(-1) for Sn(II) and 0.15 μg·mL(-1) for Sn(IV). In DMSA, ECD, MDP, and pyrophosphate, 90.0%, 64.9%, 93.2%, and 87.5%, respectively, of the tin was present as Sn(II). In this work, selective determination of Sn(II) and Sn(IV) was achieved using 2 supporting electrolytes (H(2)SO(4) and HCl). In 3 M H(2)SO(4), only Sn(II) produced a polarographic wave with the maximum current in -370 mV. Under the same conditions, no current could be determined for Sn(IV). In 3 M HCl, Sn(II) and Sn(IV) were electroactive and the maximum currents of the 2 waves appeared in -250 and -470 mV. No other components of the lyophilized reagents had any influence. The developed polarographic method was adequate to quantify Sn(II) and Sn(IV) in DMSA, ECD, MDP, and pyrophosphate cold kits.


Low-intensity cigarette smoking and mortality risks: a pooled analysis of prospective cohort studies in Japan.
Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood. We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model. The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk. Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD.


Noncanonical Nuclear Factor Kappa B (NF-κB) Signaling and Potential for Therapeutics in Sepsis.
NF-κB signaling plays a central role in the pathophysiology of severe sepsis and septic shock. Despite tremendous and missed efforts, novel therapeutics for severe sepsis and septic shock are still needed. Many drugs have been designed to target the canonical NF-κB signaling pathway with limited success, potentially due to the nonspecificity of the drugs for other kinases and the interaction of canonical signaling with other pathways. Here, we review the canonical and noncanonical signaling pathways of NF-κB, the cross talk and negative regulation of the two pathways, and the potential for therapeutics arising from the noncanonical NF-κB pathway in relation to the pathophysiology of septic shock.


Light and electron microscopical localization of concanavalin A lectin binding sites in rat epiphyseal chondrocytes.
Concanavalin A lectin binding sites have been detected within the cytoplasm of epiphyseal chondrocytes. Correlative light and electron microscopic results were obtained, indicating the presence of alpha-D-mannose and/or alpha-D-glucose residues detected by the lectin in the rough endoplasmic reticulum region. Quantitation of the electron microscopic cytochemical reaction also showed that the specific labelling was almost exclusively localized in the lumen of endoplasmic reticulum cisternae. No significant staining was found in other membrane compartments or extracellular matrix. This labelling pattern could be considered as the cytochemical evidence of N-glycosylation processes occurring during the biosynthesis of cartilage extracellular matrix components by chondrocytes.


miR-101a and miR-30b contribute to inflammatory cytokine-mediated β-cell dysfunction.
Inflammatory cytokines have a critical role in the progressive deterioration of pancreatic β-cell function and development of type 1 diabetes. Prolonged exposure of β-cells to inflammatory cytokines results in gene expression modifications, leading to loss of β-cell function. MicroRNAs (miRNAs) are small non-coding RNAs acting as key regulators of gene expression. Here, we demonstrate that miR-101a and miR-30b are key players in cytokine-mediated β-cell dysfunction. We found that IL-1β induces an increase in miR-101a and miR-30b in MIN6 cells, and that the two miRNAs participate in β-cell dysfunction, including decreased insulin content, gene expression, and increased β-cell death. miR-101a and miR-30b reduce proinsulin expression and insulin content by directly targeting the transcriptional factor Neurod1. In addition, β-cell apoptosis mediated by miR-101a and miR-30b is associated with diminished expression level of the antiapoptotic protein Bcl2. Moreover, we show that miR-101a causes an impairment in glucose-induced insulin secretion by decreasing the expression of the transcription factor Onecut2. Taken together, our findings suggest that changes in the levels of miR-101a and miR-30b contribute to cytokine-mediated β-cell dysfunction occurring during the development and progression of type 1 diabetes.


Effect of the intrauterine contraceptive device on protein components of human uterine fluid.
The albumin, immunoglobulin G (IgG), immunoglobulin A (IgA), lysozyme, lactoferrin, alpha 1-antitrypsin, alpha 1x-antichymotrypsin, and neutral proteinase levels of uterine fluid and serum of IUD-bearing women were studied in relationship to the phase of the menstrual cycle, the length of IUD implantation and the presence of reported side effects. Selection of these proteins was based on their potential importance in IUD-induced contraceptive action and/or side effects. Generally, only small differences were found in the serum levels of these proteins during the cycle, with different length of implantation or between patients with and without side effects. However, transudation of proteins (albumin, IgG, alpha 1-antitrypsin, alpha 1x-antichymotrypsin) from blood into the uterine cavity was enhanced by the IUD, especially during the postmenstrual and premenstrual periods. The IUD enhanced the local secretory response even more, i.e., the increased release of proteins from the endometrium (lysozyme, neutral proteinase, IgA) and from leukocytes (lysozyme, lactoferrin). Protein changes occurred as the period of insertion increased. These changes in the uterine milieu may account in part for the contraceptive action of the IUD. The secretory proteins rather than the transudation products differed between patients who showed IUD-associated side effects vs. those who did not, implying that IUD-related pathology is primarily associated with changes in local secretory response. The possible role of each protein in the mechanism of IUD action is presented in view of the present findings.


A pilot study of falls risk and vestibular dysfunction in older fallers presenting to hospital emergency departments.
To compare falls risk in older fallers and non-fallers, with an emphasis on dizziness and signs of vestibular dysfunction. The fallers had presented to the Emergency Department of the Royal Melbourne Hospital, Australia following a fall and were discharged directly home (n = 20) (75% female, mean age 78 years). The non-fallers were an age and gender matched group, who had not fallen in the past 12 months (n = 20). All clients received a home-based assessment, which involved a comprehensive assessment of falls risk. Over three-quarters of the fallers took four or more medications, had balance impairments, and used a gait aid in the community. The fallers had a significantly higher falls risk score (P < 0.001), demonstrated significantly poorer balance (P < 0.001) and walked significantly more slowly (P < 0.001) than the non-fallers. There was no significant difference between the groups in their reports of dizziness (P = 0.68), although static balance testing (CTSIB condition 5) suggested a greater degree of underlying vestibular dysfunction in the group of fallers (P < 0.001). Older people discharged home from the ED following a fall are at high risk of falling in the future and have a greater level of vestibular dysfunction based on simple clinical testing. Additional clinically applicable tests of vestibular function are required to further investigate the relationship between vestibular dysfunction and falling in older people.


All Solution-Processed Inorganic, Multilevel Memristors Utilizing Liquid Metals Electrodes Suitable for Analog Computing.
Herein, we report a solution-processable memristive device based on bismuth vanadate (BiVO4) and titanium dioxide (TiO2) with gallium-based eutectic gallium-indium (EGaIn) and gallium-indium-tin alloy (GaInSn) liquid metal as the top electrode. Scanning electron microscopy (SEM) shows the formation of a nonporous structure of BiVO4 and TiO2 for efficient resistive switching. Additionally, the gallium-based liquid metal (GLM)-contacted memristors exhibit stable memristor behavior over a wide temperature range from -10 to +90 °C. Gallium atoms in the liquid metal play an important role in the conductive filament formation as well as the device's operation stability as elucidated by I-V characteristics. The synaptic behavior of the GLM-memristors was characterized, with excellent long-term potentiation (LTP) and long-term depression (LTD) linearity. Using the performance of our device in a multilayer perceptron (MLP) network, a ∼90% accuracy in the handwriting recognition of modified national institute of standards and technology database (MNIST) was achieved. Our findings pave a path for solution-processed/GLM-based memristors which can be used in neuromorphic applications on flexible substrates in a harsh environment.


Interexamination repeatability and spatial heterogeneity of liver iron and fat quantification using MRI-based multistep adaptive fitting algorithm.
To assess the interexamination repeatability and spatial heterogeneity of liver iron and fat measurements using a magnetic resonance imaging (MRI)-based multistep adaptive fitting algorithm. This prospective observational study was Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant. Written informed consent was waived. In all, 150 subjects were imaged on 3T MRI systems. A whole-liver volume acquisition was performed twice using a six-echo 3D spoiled gradient echo sequence during two immediately adjacent examinations. Colocalized regions of interest (ROIs) in three different hepatic segments were placed for R2 * and proton density fat fraction (PDFF) measurements by two readers independently. Mean R2 * and PDFF values between readers and acquisitions were compared using the Wilcoxon signed-rank test, intraclass correlation coefficients (ICCs), linear regression, Bland-Altman analysis, and analysis of variance (ANOVA). The mean R2 * and PDFF values across all ROIs and measurements were 51.2 ± 25.2 s(-1) and 6.9 ± 6.4%, respectively. Mean R2 * and PDFF values showed no significant differences between the two acquisitions (P = 0.05-0.87). Between the two acquisitions, R2 * and PDFF values demonstrated almost perfect agreement (ICCs = 0.979-0.994) and excellent correlation (R(2) = 0.958-0.989). Bland-Altman analysis also demonstrated excellent agreement. In the ANOVA, the individual patient and ROI location were significant effects for both R2 * and PDFF values (P < 0.05). MRI-based R2 * and PDFF measurements are repeatable between examinations. Between-measurement changes in R2 * of more than 10.1 s(-1) and in PDFF of more than 1.7% are likely due to actual tissue changes. Liver iron and fat content are variable between hepatic segments.


Production of thiol-penicillin-binding protein 3 of Escherichia coli using a two primer method of site-directed mutagenesis.
The active site serine residue of penicillin-binding protein 3 of Escherichia coli that is acylated by penicillin (Ser-307) has been converted to a cysteine residue using a simple and efficient two primer method of site-directed mutagenesis. The resulting thiol-penicillin-binding protein 3 was expressed under the control of the lacUV5 promoter in a high copy number plasmid. Constitutive expression of the thiol-enzyme (but not of the wild-type enzyme) was lethal, and the plasmid could only be maintained in E. coli strains that carried the lacIq mutation. Induction of the expression of the thiol-enzyme resulted in inhibition of cell division and the growth of the bacteria into very long filamentous cells. The inhibition of septation was probably due to interference of the function of the wild-type penicillin-binding protein 3 in cell division by the enzymatically inactive thiol-enzyme, and this implies that penicillin-binding protein 3 acts as part of a complex in vivo. We were unable to detect any acylation of the thiol-enzyme by penicillin, but it is not yet clear if this was because the thioester was not formed at an appreciable rate, or if it was formed but was too unstable to be detected by a modified penicillin-binding protein assay.


Designing a Co-created Intervention to Promote Motivation and Maintenance of Time-Restricted Eating in Individuals With Overweight and Type 2 Diabetes.
To design an appealing time-restricted eating (TRE) intervention by exploring behavioral and social mechanisms to improve TRE adoption and maintenance among people with type 2 diabetes (T2D) and overweight. Time-restricted eating is an intermittent fasting regimen suggested to improve glycemic control and body weight. Intervention development combined coherence theory and empirical data (workshops and semistructured interviews with the target group, their relatives, and health care professionals [HCPs]). Abductive analysis was applied. The analysis suggested designing the TRE intervention in 2 phases: a short period with strict TRE, followed by a longer period focusing on adapting TRE to individual needs with support from HCPs, relatives, and peers. To reinforce TRE motivation and maintenance, HCPs should adopt a whole-person approach that focuses on participants' previous experiences. Important intervention elements to promote TRE adoption and maintenance are suggested to include a 2-phase design and support from professionals, family, and peers.


Effect of Dickkopf-1 and colony stimulating factor-2 on the developmental competence, quality, gene expression and live birth rate of buffalo (Bubalus bubalis) embryos produced by hand-made cloning.
A functional canonical WNT signaling pathway exists in preimplantation embryos and inhibits embryonic development. Recent studies suggest that this pathway is over-expressed in nuclear transferred (NT), compared to IVF embryos. The present study investigated the effects of Dickkopf-1 (DKK1), an inhibitor of canonical WNT signaling pathway and colony stimulating factor-2 (CSF2), an embryokine, on the developmental competence, quality, gene expression and live birth rate of NT buffalo embryos produced by Hand-made cloning (HMC). Following supplementation of the in vitro culture medium on day 5 with DKK1 (100 ng/mL), CSF2 (10 ng/mL), DKK1+CSF2 or no supplementation (control), the blastocyst rate was higher (P < 0.05) with DKK1 and DKK1+CSF2 (42.6 ± 1.4% and 46.6 ± 0.9%, respectively) than with CSF2 or controls (40.6 ± 1.3% and 39.0 ± 1.3%, respectively). The apoptotic index of the blastocysts was lower (P < 0.05) for DKK1, CSF2 and DKK1+CSF2 groups (3.44 ± 0.14, 3.39 ± 0.11 and 3.11 ± 0.22, respectively) compared to controls (6.64 ± 0.25), and was similar to that of the IVF blastocysts (3.67 ± 0.18). Although the total cell number was similar for the DKK1, CSF2, DKK1+CSF2 and control groups (200.4 ± 3.05, 196.4 ± 3.73, 204.7 ± 3.71 and 205 ± 4.03, respectively), the inner cell mass:trophectoderm cell number ratio of DKK1, CSF2 and DKK1+CSF2 groups (0.21 ± 0.01, 0.17 ± 0.01 and 0.22 ± 0.02, respectively) was higher (P < 0.05) than controls (0.13 ± 0.01) and was similar to that of IVF blastocysts (0.19 ± 0.01). Treatment with DKK1 or CSF2 or both increased (P < 0.05) the expression level of OCT4, NANOG,SOX2, GATA6, BCL2, PTEN, P53, FGF4, GLUT1 and IFN-τ, and decreased that of C-MYC, CDX2, CASPASE, DNMT3a, TCF7 and LEF1 in blastocysts, compared to controls. Transfer of DKK1-treated embryos to 13 recipients resulted in 4 pregnancies (30.8%; 2 live births, one abortion and one currently at 9 months of pregnancy) whereas, transfer of DKK1+CSF2-treated embryos to 16 recipients, resulted in 4 pregnancies (25.0%), all of which resulted in live births. No pregnancy was obtained after transfer of control and CSF-treated embryos to 12 and 16 recipients, respectively. These results suggest that DKK1 treatment of NT embryos increases the blastocyst, conception and live birth rate, and improves their quality whereas, CSF2 treatment, does not affect the blastocyst, conception and live birth rate despite improvement in embryo quality.


Identification and preliminary mapping with monoclonal antibodies of a herpes simplex virus 2 glycoprotein lacking a known type 1 counterpart.
The properties of herpes simplex virus 2 (HSV-2)-specific proteins reactive with monoclonal antibody H966 derived from mice immunized with HSV-2 strain G are reported. The reactive proteins contained in infected cell lysates subjected to electrophoresis in denaturing gels and transferred to nitrocellulose sheets form a relatively sharp band characteristic of Mr 124,000 proteins and a diffuse, more slowly migrating band. Antigens reactive with H966 were detected on the surface of viable, unfixed cells. The electrophoretic mobility of the H966-reactive proteins made in the presence of tunicamycin was more rapid than that of the proteins made in the absence of the drug. Direct evidence that the HSV-2-specific antigen was a glycoprotein emerged from purification of [14C]glucosamine-labeled proteins with similar electrophoretic mobilities by immunoabsorption to H966 bound to Sepharose beads. Analyses of the reactivity of HSV-1 X HSV-2 recombinants indicated the gene specifying the glycoprotein maps in the S component of the DNA. The glycoprotein detected by H966 has no known counterpart in HSV-1 and corresponds to the glycoprotein previously designated as gC of HSV-2 and reported to map to the right of gC specified by HSV-1. Inasmuch as an HSV-2 gene colinear with HSV-1 gC has been reported to specify a glycoprotein currently designated as gC of HSV-2 by Para et al. [J. Virol. 45, 1223-1227 (1983)], the glycoprotein identified by H966 should be designated as gG.


Interprofessional collaboration: issues for practice and research.
SUMMARY The current health care system is based on accountability, cost containment, and quality of care. Collaborative practice models may be a viable means for improving health care delivery. The purpose of this paper is to outline how interprofessional education, practice, and research can establish economic benefits and effective clinical outcomes outside of discipline specific investigation.


Functional idiosyncrasies of tRNA isoacceptors in cognate and noncognate aminoacylation systems.
The specificity of transfer RNA aminoacylation by cognate aminoacyl-tRNA synthetase is a crucial step for synthesis of functional proteins. It is established that the aminoacylation identity of a single tRNA or of a family of tRNA isoacceptors is linked to the presence of positive signals (determinants) allowing recognition by cognate synthetases and negative signals (antideterminants) leading to rejection by the noncognate ones. The completion of identity sets was generally tested by transplantation of the corresponding nucleotides into one or several host tRNAs which acquire as a consequence the new aminoacylation specificities. Such transplantation experiments were also useful to detect peculiar structural refinements required for optimal expression of a given aminoacylation identity set within a host tRNA. This study explores expression of the defined yeast aspartate identity set into different tRNA scaffolds of a same specificity, namely the four yeast tRNA(Arg) isoacceptors. The goal was to investigate whether expression of the new identity is similar due to the unique specificity of the host tRNAs or whether it is differently expressed due to their peculiar sequences and structural features. In vitro transcribed native tRNA(Arg) isoacceptors and variants bearing the aspartate identity elements were prepared and their aminoacylation properties established. The four wild-type isoacceptors are active in arginylation with catalytic efficiencies in a 20-fold range and are inactive in aspartylation. While transplanted tRNA(1)(Arg) and tRNA(4)(Arg) are converted into highly efficient substrates for yeast aspartyl-tRNA synthetase, transplanted tRNA(2)(Arg) and tRNA(3)(Arg) remain poorly aspartylated. Search for antideterminants in these two tRNAs reveals idiosyncratic features. Conversion of the single base-pair C6-G67 into G6-C67, the pair present in tRNA(Asp), allows full expression of the aspartate identity in the transplanted tRNA(2)(Arg), but not in tRNA(3)(Arg). It is concluded that the different isoacceptor tRNAs protect themselves from misaminoacylation by idiosyncratic pathways of antidetermination.


Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization.
Patients with heart failure are frequently hospitalized for fluid overload. A reliable method for chronic monitoring of fluid status is therefore desirable. We evaluated an implantable system capable of measuring intrathoracic impedance to identify potential fluid overload before heart failure hospitalization and to determine the correlation between intrathoracic impedance and standard measures of fluid status during hospitalization. Thirty-three patients with NYHA class III and IV heart failure were implanted with a special pacemaker in the left pectoral region and a defibrillation lead in the right ventricle. Intrathoracic impedance was regularly measured and recorded between the lead and the pacemaker case. During hospitalizations, pulmonary capillary wedge pressure and fluid status were monitored. Ten patients were hospitalized for fluid overload 25 times over 20.7+/-8.4 months. Intrathoracic impedance decreased before each admission by an average of 12.3+/-5.3% (P<0.001) over an average of 18.3+/-10.1 days. Impedance reduction began 15.3+/-10.6 days (P<0.001) before the onset of worsening symptoms. There was an inverse correlation between intrathoracic impedance and pulmonary capillary wedge pressure (r=-0.61, P<0.001) and between intrathoracic impedance and net fluid loss (r=-0.70, P<0.001) during hospitalization. Automated detection of impedance decreases was 76.9% sensitive in detecting hospitalization for fluid overload, with 1.5 false-positive (threshold crossing without hospitalization) detections per patient-year of follow-up. Intrathoracic impedance is inversely correlated with pulmonary capillary wedge pressure and fluid balance and decreased before the onset of patient symptoms and before hospital admission for fluid overload. Regular monitoring of impedance may provide early warning of impending decompensation and diagnostic information for titration of medication.


A retrospective observational study of intraductal breast papilloma and its coexisting lesions: A real-world experience.
Breast intraductal papilloma is a heterogeneous group. The aim of the study is to investigate the intraductal breast papilloma and its coexisting lesions retrospectively in real-world practice. We retrospectively identified 4450 intraductal breast papilloma and its coexisting lesions. About 18.36% of intraductal papilloma coexisted with malignant lesions of the breast, 37.33% coexisted with atypia hyperplasia (AH), 25.24% coexisted with benign lesions, and only 19.10% coexisted without concomitant lesions. In addition, 36.80% of intraductal breast papilloma had nipple discharge, 51.46% had a palpable breast mass, and 16.45% had both nipple discharge and a palpable breast mass. About 28.18% experienced discomfort or were asymptomatic. Furthermore, 98.99% had ultrasound abnormalities, and 53.06% had intraductal hypoechogenicity upon ultrasound. 31.89% had mammographic distortion, and 14.45% had microcalcification upon mammography. Intraductal breast papilloma with malignancy had significant correlations with clinical manifestations. Coexisting malignancy was also related to ultrasound abnormality (BIRADS 4C and 5), mammographic distortion, and microcalcification upon mammography but was not related to the intraductal hypoechoic upon ultrasound. Coexisting atypical hyperplasia correlated with nipple discharge but not palpable mass, mammographic distortion, or intraductal hypoechoic upon ultrasound. The coexisting AH was also related to abnormality upon ultrasound or microcalcification compared with the benign lesions. The intraductal papilloma coexists with malignancy or AH accounted for more than 50%, and the clinical information on papilloma and its coexisting lesions is nonspecific. We recommended surgical treatment for benign intraductal papillary lesions.


Differential contribution of osteoclast- and osteoblast-lineage cells to CpG-oligodeoxynucleotide (CpG-ODN) modulation of osteoclastogenesis.
CpG-ODNs modulate osteoclast differentiation through Toll-like receptor 9 (TLR9). Using TLR9-deficient mice, we found that activation of TLR9 on both osteoclast precursors and osteoblasts mediate the osteoclastogenic effect of CpG-ODN. Osteoclastic TLR9 is more important for this activity. Bacterial infections cause pathological bone loss by accelerating differentiation and activation of the osteoclast. A variety of bacteria-derived molecules have been shown to enhance osteoclast differentiation through activation of Toll-like receptors (TLRs). We have shown that CpG-oligodeoxynucleotides (CpG-ODNs), mimicking bacterial DNA and exerting their cellular activities through TLR9, modulate osteoclast differentiation in a complex manner: the ODNs inhibit the activity of the physiological osteoclast differentiation factor RANKL in early osteoclast precursors (OCPs) but markedly stimulate osteoclastogenesis in cells primed by RANKL. Osteoclast precursors and osteoblasts from TLR9-deficient (TLR9-/-) and wildtype (TLR9+/+) mice were used for in vitro analyses of osteoclast differentiation and modulation of signal transduction and gene expression. As expected CpG-ODN did not exert any activity in cells derived from TLR9-/-mice; these cells, however, responded in a normal manner to other stimuli. Using bone marrow/osteoblasts co-cultures from all possible combinations of TLR9-/- and TLR9+/+ mice-derived cells, we showed that TLR9 in the two lineages is required for CpG-ODN induction of osteoclastogenesis. CpG-ODN modulates osteoclastogenesis in a TLR9-dependent manner. Activation of TLR9 in bone marrow-derived osteoclasts precursors is more crucial to induction of osteoclastogenesis than activation of the osteoblastic TLR9.


Leveraging technology: A multi-component personalized system of instruction to teach sight words.
Technology-enabled personalized systems of instruction (PSI) could streamline resource-intensive instructional strategies, potentially easing their delivery and accelerating student learning. This study evaluated the effectiveness and efficiency of a PSI that incorporated adaptive assessment, incremental rehearsal, and peer-assisted learning to teach sight words. Participants in grades 1-3 were randomly assigned to either a control condition or treatment condition. In the treatment condition, participants engaged in the PSI in dyads, working at their instructional level with minimal adult supervision. Compared to the control condition, target learners engaging in the PSI acquired previously unknown sight words, then maintained and generalized the words 30 days post-intervention with a moderate main effect (β = 0.28). On average, participants rated the PSI as positive or very positive. The potential for PSIs to make instructional activities more efficient, effective, and individualized is discussed.


Planning dementia services: new estimates of current and future prevalence rates of dementia for Ireland.
The paper provides new estimates of dementia prevalence at a national and local level in Ireland and new projections of future numbers of people with dementia. The prevalence of dementia at a national and local level has been calculated by applying European Collaboration on Dementia (EuroCoDe) prevalence rates to data from the Census of Population 2006. The National Disability Survey has been used to estimate the number of people with Down syndrome and dementia. Projections of future numbers of people with dementia have been calculated by applying EuroCoDe prevalence rates to the most recently available population projections from the Central Statistics Office (CSO). It is estimated that there were 41 740 people with dementia in Ireland in 2006. Estimates show that there are clear regional differences in prevalence of dementia across Ireland, with the largest proportion of people with dementia in the West of Ireland, and the Dublin North Eastern region having the lowest share of dementia. Our best estimate is that there are 700 people with Down syndrome and dementia in Ireland. Applying EuroCoDe prevalence rates to the most recent CSO population projections shows that the prevalence of dementia in Ireland will increase to between 67 493 and 70 000 in 2021 and to between 140 580 and 147 000 in 2041. Although there are several limitations to these estimates, the data provide timely and useful information for planning effective health and social care services, as well as raising public and professional awareness about dementia at a national level.


The Correlation Between Petrous Part of the Temporal Bone Density and the Internal Auditory Canal Diameter in Sensorineural Hearing Loss Patients with Chronic Renal Failure.
Patients with chronic renal failure often suffer from hearing loss and the most common cause is sensorineural hearing loss. Sensorineural hearing loss can be caused by cochlear otosclerosis with early symptoms such as decreased petrous part of the temporal bone density due to narrowing of the internal auditory canal. Finding a correlation between the petrous part of the temporal bone density and the anteroposterior diameter of the internal auditory canal in sensorineural hearing loss in patients with chronic renal failure. An observational analytic, cross-sectional study, using a consecutive sampling technique. The petrous part of the temporal bone density decreased in patients with chronic renal failure. The anteroposterior diameter of the internal auditory canal remained normal, there was no association with sensorineural loss. There is a significant correlation between the petrous part of the temporal bone density and sensorineural hearing loss in patients with chronic renal failure. High-resolution CT scans of the mastoid can assist clinicians in determining cochlear otosclerosis and the subsequent detection of the early presence of sensorineural hearing loss.


P21-activated kinase 2-mediated β-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer.
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used for treating patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, acquired resistance to osimertinib is inevitable in EGFR-mutant NSCLC. By employing a global mass spectrometry-based phosphoproteomics approach, we identified that the activated p21-activated kinase 2 (PAK2)/β-catenin axis acts as a driver of osimertinib resistance. We found that PAK2 directly phosphorylates β-catenin and increases the nuclear localization of β-catenin, leading to the increased expression and transcriptional activity of β-catenin, which in turn enhances cancer stem-like properties and osimertinib resistance. Moreover, we revealed that HER3 as an upstream regulator of PAK2, drives the activation of PAK2/β-catenin pathways in osimertinib-resistant cells. The clinical relevance of these findings was further confirmed by examining tissue specimens from patients with EGFR-mutant NSCLC. The results demonstrated that the levels of HER3, phospho-PAK2 (p-PAK2) and β-catenin in the tissues from patients with EGFR-mutant NSCLC, that had relapsed after treatment with osimertinib, were elevated compared to those of the corresponding untreated tissues. Additionally, the high levels of HER3, p-PAK2 and β-catenin correlated with shorter progression-free survival (PFS) in patients with EGFR-TKI-treated NSCLC. We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of β-catenin is important for osimertinib resistance and targeting the HER3/PAK2/β-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.


Exploratory analysis of textual data from the Mother and Child Handbook using a text mining method (II): Monthly changes in the words recorded by mothers.
The aim of the study was to examine the possibility of converting subjective textual data written in the free column space of the Mother and Child Handbook (MCH) into objective information using text mining and to compare any monthly changes in the words written by the mothers. Pregnant women without complications (n = 60) were divided into two groups according to State-Trait Anxiety Inventory grade: low trait anxiety (group I, n = 39) and high trait anxiety (group II, n = 21). Exploratory analysis of the textual data from the MCH was conducted by text mining using the Word Miner software program. Using 1203 structural elements extracted after processing, a comparison of monthly changes in the words used in the mothers' comments was made between the two groups. The data was mainly analyzed by a correspondence analysis. The structural elements in groups I and II were divided into seven and six clusters, respectively, by cluster analysis. Correspondence analysis revealed clear monthly changes in the words used in the mothers' comments as the pregnancy progressed in group I, whereas the association was not clear in group II. The text mining method was useful for exploratory analysis of the textual data obtained from pregnant women, and the monthly change in the words used in the mothers' comments as pregnancy progressed differed according to their degree of unease.


Pharmacophore mapping, molecular docking, chemical synthesis of some novel pyrrolyl benzamide derivatives and evaluation of their inhibitory activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis.
In an effort to produce new lead antimycobacterial compounds, herein we have reported the synthesis of a sequence of new pyrrolyl benzamide derivatives. The new chemical entities were screened to target enoyl-ACP reductase enzyme, which is one of the key enzymes of M. tuberculosis that are involved in type II fatty acid biosynthetic pathway. Compound 3q exhibited H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that binds the active site of InhA. All the pyrrolyl benzamide compounds were evaluated as inhibitors of M. tuberculosis H37Rv as well as inhibitors of InhA. Among them, few representative compounds were tested for mammalian cell toxicity on the human lung cancer cell-line (A549) and MV cell line that presented no cytotoxicity. Five of these compounds exhibited a good activity against InhA.


First-Step Results of Children Presenting with Bleeding Symptoms or Abnormal Coagulation Tests in an Outpatient Clinic.
Mild bleeding symptoms are commonly seen in the general population. The aim of this study was to determine the final clinical and laboratory features of children referred for a first evaluation with a suspected bleeding disorder in the pediatric outpatient clinic of İstanbul University. The medical records of 26,737 outpatients who were admitted to the Division of Ambulatory Pediatrics between 31 October 2011 and 31 October 2012 were evaluated retrospectively. Ninety-nine patients were initially diagnosed as having probable bleeding disorders and were followed up. The symptoms of bleeding in addition to coagulation tests were analyzed. Of the 99 patients, 52 (52.5%) were male and 47 were female, and the mean age of the entire study group was 9.1±4.1 years (minimum-maximum: 2-18 years). Major bleeding symptoms were epistaxis in 36 patients (36.4%), easy bruising in 32 (32.3%), and menorrhagia in 6 (6.1%). After initial tests ordered by the pediatrician, 36 of 99 patients (36.4%) were diagnosed as having bleeding disorders that included von Willebrand disease in 12 (12.1%), hemophilia A or B in 9 (9.1%), and other rare factor deficiencies in 9 (9.1%). Six patients (6.1%) were found to have combined deficiencies. Seven of 36 patients had a family history of bleeding. Among the patients referred for bleeding disorders, 36.4% were diagnosed with a bleeding disorder with the help of primary screening tests ordered in the outpatient clinic.


Different lasers reveal different skin microcirculatory flowmotion - data from the wavelet transform analysis of human hindlimb perfusion.
Laser Doppler flowmetry (LDF) and reflection photoplethysmography (PPG) are standard technologies to access microcirculatory function in vivo. However, different light frequencies mean different interaction with tissues, such that LDF and PPG flowmotion curves might have distinct meanings, particularly during adaptative (homeostatic) processes. Therefore, we analyzed LDF and PPG perfusion signals obtained in response to opposite challenges. Young healthy volunteers, both sexes, were assigned to Group 1 (n = 29), submitted to a normalized Swedish massage procedure in one lower limb, increasing perfusion, or Group 2 (n = 14), submitted to a hyperoxia challenge test, decreasing perfusion. LDF (Periflux 5000) and PPG (PLUX-Biosignals) green light sensors applied distally on both lower limbs recorded perfusion changes for each experimental protocol. Both techniques detected the perfusion increase with massage, and the perfusion decrease with hyperoxia, in both limbs. Further analysis with the wavelet transform (WT) revealed better depth-related discriminative ability for PPG (more superficial, less blood sampling) compared with LDF in both challenges. Spectral amplitude profiles consistently demonstrated better sensitivity for LDF, especially regarding the lowest frequency components. Strong correlations between components were not found. Therefore, LDF and PPG flowmotion curves are not equivalent, a relevant finding to better study microcirculatory physiology.


Control of placental glucose transfer.
There is little evidence to suggest that the membrane transfer mechanism of the placenta for glucose becomes saturated until maternal blood glucose concentrations are quite high. Also, recent evidence suggests that the membrane transport system for glucose in the placenta is not stimulated by maternal or fetal insulin. Furthermore, there is no solid evidence that hormonal or non-hormonal factors function in vivo to limit membrane transport of glucose in the placenta. Therefore, the limited data which are available suggest that there are no specific mechanisms which acutely regulate placental membrane transport of glucose, and that this membrane transport mechanism operates to maximize maternal-to-fetal glucose transfer. The rate of maternal-to-fetal glucose transfer is a function of the transplacental concentration gradient. This gradient appears to be under the control of fetal insulin and placental lactogen. The available data suggest that both hormones act to increase this concentration gradient: insulin by decreasing fetal blood glucose, and placental lactogen by both decreasing fetal and increasing maternal blood glucose concentrations. Furthermore, high rates of glucose uptake by fetal erythrocytes tend to promote maintenance of this concentration gradient. Therefore, these influences of the maternal-fetal concentration gradient promote transplacental glucose flux to the fetus. As illustrated by the fetal complications associated with maternal hyperglycaemia, the cellular and organismic physiology of the fetus and placenta appears to maximize, rather than optimize, glucose availability to the fetus. It may be, however, that during normal pregnancy, maximal availability is optimal for fetal development.


[A procedure for determining the dose distribution behind block shields. I. A computational method of determining the scatter distribution of a 60Co pencil beam].
The energy dose distribution of a photon pencil beam ray for photons with the primary energy of 1.25 MeV is determined using the Monte-Carlo-method. The found energy dose distribution underlies the calculation of spreading additive-air-ratio for extended 60Co-irradiation fields. The spreading additive-air-ratios, found by the model, show good correspondence with known values from literature.


Leflunomide prevents the development of experimentally induced myasthenia gravis.
Myasthenia gravis is an autoimmune disease in which autoantibodies specific to the acetylcholine receptor (AChR) are formed, leading to a gradual destruction of the receptors in muscles that are responsible for picking up nerve impulses, and results in weakness and eventual loss of muscle function. The novel immunomodulating drug leflunomide (HWA 486) has been shown to be very effective in preventing and halting ongoing disease in an array of experimental autoimmune disorders and reactions leading to organ graft rejection. Further, recent data from phase II clinical trials indicate that this drug is efficacious and is safe in humans with rheumatoid arthritis. In the studies reported here, we found that rats immunized with AChR-protein and not receiving leflunomide developed experimental myasthenia gravis (EMG) between day 7 and 11 post-immunization, and about 79% of these animals expressed clinical signs of disease. Treatment of AChR-protein immunized rats with leflunomide, from the day of disease induction, totally suppressed the development of EMG. Thus, the results we have obtained using leflunomide in EMG indicate that this drug could be beneficial in combating myasthenia gravis in humans.


Mismatch-fueled catalytic hairpin assembly mediated ultrasensitive biosensor for rapid detection of MicroRNA.
Herein, a mismatch-fueled catalytic hairpin assembly (MCHA) was rationally engineered, which possessed higher amplification efficiency and faster rate than catalytic hairpin assembly (CHA). Once input target microRNA-21(miRNA-21) triggers the MCHA, the hairpin DNA H1 will be opened to form the duplex H1-miRNA-21, then the mismatched hairpin DNA H2 could easily hybridize with H1-miRNA-21 to generate duplex H1-H2 and the miRNA-21 could be released to enter next cycle, thus generating amounts of output products. Impressively, the MCHA realizes a pretty shorter complete reaction time of 40 min and quite higher amplification efficiency of 9.56 × 106, which dramatically transcended the barrier: low amplification times and long reaction time in traditional CHA. As a proof of the concept, the elaborated MCHA as a hyper-efficiency and high-speed DNA signal-magnifier was successfully applied in ultrasensitive and rapid detection of miRNA-21 with the detection limit of 0.17 fM, which exploited an ingenious nucleic acid signal amplification technique for sensitive and fast detection of biomarkers in biosensing assay and clinic diagnose.


Single cell profiling of CD45+ spinal cord cells reveals microglial and B cell heterogeneity and crosstalk following spinal cord injury.
Immune cells play crucial roles after spinal cord injury (SCI). However, incomplete knowledge of immune contributions to injury and repair hinders development of SCI therapies. We leveraged single-cell observations to describe key populations of immune cells present in the spinal cord and changes in their transcriptional profiles from uninjured to subacute and chronic stages of SCI. Deep-read single-cell sequencing was performed on CD45+ cells from spinal cords of uninjured and injured Swiss-webster mice. After T9 thoracic contusion, cells were collected 3-, 7-, and 60-day post-injury (dpi). Subpopulations of CD45+ immune cells were identified informatically, and their transcriptional responses characterized with time. We compared gene expression in spinal cord microglia and B cell subpopulations with those in published models of disease and injury. Microglia were compared with Disease Associated Microglia (DAM) and Injury Responsive Microglia (IRM). B cells were compared to developmental lineage states and to an Amyotrophic Lateral Sclerosis (ALS) model. In uninjured and 7 dpi spinal cord, most CD45+ cells isolated were microglia while chronically B cells predominated. B cells accumulating in the spinal cord following injury included immature B to mature stages and were predominantly found in the injury zone. We defined diverse subtypes of microglia and B cells with altered gene expression with time after SCI. Spinal cord microglia gene expression indicates differences from brain microglia at rest and in inflammatory states. Expression analysis of signaling ligand-receptor partners identified microglia-B cell interactions at acute and chronic stages that may be involved in B cell recruitment, retention, and formation of ectopic lymphoid follicles. Immune cell responses to SCI have region-specific aspects and evolve with time. Developmentally diverse populations of B cells accumulate in the spinal cord following injury. Microglia at subacute stages express B cell recruitment factors, while chronically, they express factors predicted to reduce B cell inflammatory state. In the injured spinal cord, B cells create ectopic lymphoid structures, and express secreted factors potentially acting on microglia. Our study predicts previously unidentified crosstalk between microglia and B cells post-injury at acute and chronic stages, revealing new potential targets of inflammatory responses for SCI repair warranting future functional analyses.


Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment.
Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.


Clindamycin-associated colitis in hamsters: protection with vancomycin.
Clindamycin and lincomycin produced a lethal enterocolitis in 65 of 67 Syrian hamsters. The administration of oral or parenteral vancomycin to recipients of clindamycin or lincomycin was uniformly protective in 49 patients. These results suggest that certain bacteria play a role in the pathogenesis of enterocolitis in this model.


Transdermal delivery of naloxone hydrochloride using minimally invasive physical ablation techniques.
NAL's hydrophilicity and the inherent lipophilic properties of the stratum corneum hinders its capacity for immediate delivery through skin in opioid rescue cases. In this study, we had sought to investigate the feasibility of using minimally invasive physical ablative techniques including sonophoresis, laser, dermaplaning, microneedles, and microdermabrasion for systemically delivering NAL via the skin. These techniques reduced lag time to NAL delivery to about 3-12 min from 71.22 ± 9.62 min seen for passive delivery. Also, they all significantly enhanced the amount of NAL delivered in 1 h and over 24 h period of evaluation as compared to the passive group (p < 0.05). Sonophoresis and laser showed the greatest delivery in 1 h, followed by dermaplaning. The cumulative amount of drug delivered by these approaches in 1 h were 1277.95 ± 387.06, 83.33 ± 11.11, 30.66 ± 5.67 µg/cm2, respectively. Though the most remarkable, inconsistencies in in vitro permeation profile of NAL were observed with the 1 MHz ultrasound frequency used. With proper optimization of the conditions of use and design, the different approaches explored in this study can be potentially applied for the systemic delivery of naloxone in opioid overdose emergencies and opioid disaccustoming purposes.


Effects of superoxide radicals on transport (Na + K) adenosine triphosphatase and protection by superoxide dismutase.
Membrane (Na +K)ATPase isolated from rat brain was preincubated in a medium in which superoxide radicals were generated enzymatically. Exposure to superoxide radicals caused an irreversible inactivation, which could be prevented by further addition of superoxide dismutase. (Na + K)ATPase was also protected by addition of allopurinol, a xanthine oxidase inhibitor, during preincubation. The K-activated nitrophenylphosphatase associated with (Na + K)ATPase was also found to be inactivated by preincubation with superoxide radicals, which could be prevented by superoxide dismutase.