Epigenetic reprogramming in atherosclerosis.
Recent data support the involvement of epigenetic alterations in the pathogenesis of atherosclerosis. The most widely investigated epigenetic mechanism is DNA methylation although also histone code changes occur during the diverse steps of atherosclerosis, such as endothelial cell proliferation, vascular smooth muscle cell (SMC) differentiation, and inflammatory pathway activation. In this review, we focus on the main genes that are epigenetically modified during the atherogenic process, particularly nitric oxide synthase (NOS), estrogen receptors (ERs), collagen type XV alpha 1 (COL15A1), vascular endothelial growth factor receptor (VEGFR), and ten-eleven translocation (TET), which are involved in endothelial dysfunction; gamma interferon (IFN-γ), forkhead box p3 (FOXP3), and tumor necrosis factor-α (TNF-α), associated with atherosclerotic inflammatory process; and p66shc, lectin-like oxLDL receptor (LOX1), and apolipoprotein E (APOE) genes, which are regulated by high cholesterol and homocysteine (Hcy) levels. Furthermore, we also discuss the role of non-coding RNAs (ncRNA) in atherosclerosis. NcRNAs are involved in epigenetic regulation of endothelial function, SMC proliferation, cholesterol synthesis, lipid metabolism, and inflammatory response.


Thorough QT/QTc Evaluation of the Cardiac Safety of Enarodustat (JTZ-951), an Oral Erythropoiesis-Stimulating Agent, in Healthy Adults.
This study evaluated the effect of enarodustat on cardiac repolarization in healthy subjects. Enarodustat (20 and 150 mg [supratherapeutic dose]), placebo, and moxifloxacin (positive control, 400 mg) were administered orally to males and females (N = 54) in a crossover fashion. Continuous 12-lead Holter electrocardiogram (ECG) data were obtained before and after dosing, and blood samples were obtained for pharmacokinetic assessments of enarodustat, its circulating metabolite (R)-M2, and moxifloxacin. Central tendency analysis was performed for relevant ECG parameters, the relationship between individual-corrected interval from beginning of the QRS complex to end of the T wave in the frontal plane (QTcI, the primary end point) and plasma concentrations of enarodustat and (R)-M2 were assessed, and ECG waveforms were evaluated for morphological changes. The supratherapeutic dose resulted in 7- and 9-fold higher geometric mean maximum concentrations for enarodustat and (R)-M2, respectively, than the 20 mg dose. Based on time point analysis, the upper bound of the 2-sided 90% confidence interval (CI) for QTcI did not exceed 10 milliseconds at any of the time points for either dose. Based on QTcI-concentration analysis, the slopes for enarodustat and (R)-M2 were not statistically different than 0, and the upper bounds of the 2-sided 90% CI for QTcI at the geometric mean maximum concentrations for the supratherapeutic dose were 1.97 and 1.68 milliseconds for enarodustat and (R)-M2, respectively. The lower bound of the 2-sided 90% CI for moxifloxacin was ≥5 milliseconds, demonstrating assay sensitivity. The study demonstrated no clinically relevant effect of enarodustat and (R)-M2 on cardiac repolarization. There was no evidence of any clinically significant effect on the PR interval and QRS duration, and ECG waveforms showed no new clinically relevant morphological changes.


Influences of spherical tip radius, contact depth, and contact area on nanoindentation properties of bone.
Nanoindentation has been widely used as a means to measure the micro-mechanical properties of bone and to predict the macroscopic properties. The role of indent depth and indenter tip geometry in measuring the hierarchical properties of bone tissue was explored experimentally using a range of spherical indenter tips of R=5, 25, 65, and 200 μm. Nanoindentation arrays, not targeted to fall on specific structures or locations, enabled statistical sampling of osteons within PMMA-embedded, bovine, cortical bone on a single sample to a range of maximum displacements (minimum of 100 nm and maximum of 2000 nm). Elastic finite element models were then utilized to isolate the contributions of indenter tip radius, contact area, and position within the lamellar structure in comparison to the experimental results. For a small, R=5 μm indenter tip, indentation modulus consistently increased with contact depth and increased plastic deformation, resulting in an artificial increase in elastic properties. While larger radius tips (R=25, 65, and 200 μm) did not enable evaluation of a high spatial resolution on the surface, they produced data that was representative of the lower load and contact depth measurements with the smaller tip. However the sensitivity to mechanical property variations across the 2-D surface of the material was lost with increase in indenter tip size. Correspondingly, measurement variance was also decreased as the volume contributing to the indent response represented an average of surface roughness, varying mineral content, defects, and underlying tissue type and structure.


Low-dose vitamin K to augment anticoagulation control.
To determine the effect of daily low-dose oral vitamin K supplementation on reducing variations in the international normalized ratios (INRs) in patients taking warfarin. Retrospective analysis. Anticoagulation clinic in a large, private-practice hematology group. Eight motivated patients (three men, five women), aged 45-79 years, receiving anticoagulant therapy with warfarin, whose INRs had been fluctuating for reasons not associated with identifiable changes in diet, warfarin dosage, activity level, illness, or changes in drug therapy. Daily supplementation with oral vitamin K, starting with 100 microg/day Anticoagulation providers monitored INR responses; all documented INR values were included in the analysis, even those intentionally allowed outside the therapeutic range when dosages were adjusted for procedures. After dietary vitamin K supplementation, INR fluctuations diminished in nearly all patients. Overall, a significant decrease was noted in the INR standard deviation (p<0.05), and more INRs were in the therapeutic range after the start of supplementation. Allowing for small fluctuations on either side of the target range, the number of INRs within 0.2 units of the target range increased from 32% to 57% (relative increase 76%). Time in range also increased by a similar degree. Supplementation with daily low-dose oral vitamin K significantly increased the number of INRs in range as well as the time in range, and decreased INR fluctuation in this small series of selected patients.


Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents.
Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di- and tri- substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues (31 a,b) developed returned average GI50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N2 -(3-dimethylaminopropyl)-N4 -dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N4 -(3-dimethylaminopropyl)-N2 -dodecyl-6-methylpyrimidine-2,4-diamine (31 b).


Direct, precise, enzyme-free detection of miR-103-3p in real samples by microgels with highly specific molecular beacons.
Low abundance, small size, and sequence similarities render microRNA (miRNAs) detection challenging, particularly in real samples, where quantifying weakly expressed miRNAs can be arduous due to interference of more abundant molecules. The standard quantitative reverse transcription polymerase chain reaction (qRT-PCR) requires multiple steps, thermal cycles, and costly enzymatic reactions that can negatively affect results. Here we present a direct, precise, enzyme-free assay based on microgels particles conjugating molecular beacons (MB) capable of optically detecting low abundant miRNAs in real samples. We validate the applicability of microgels assay using qRT-PCR as a reference technology. As a relevant case, we chose miR-103-3p, a valuable diagnostic biomarker for breast cancer, both in serum samples and MCF7 cells. As a result, microgels assay quantifies miRNA molecules at room temperature in a single step, 1 h (vs. 4 hrs for qRT-PCR) without complementary DNA synthesis, amplification, or expensive reagents. Microgels assay exhibits femtomolar sensitivity, single nucleotide specificity, and a wide linear range (102-107 fM) (wider than qRT-PCR), with low sample consumption (2 μL) and excellent linearity (R2= 0.98). To test the selectivity of the microgel assay in real samples, MCF7 cells were considered where the pool of 8 other miRNAs were further upregulated with respect to miRNA 103-3p. In such complex environments, microgels assay selectively detects the miRNA target, mainly due to MB advanced stability and specificity as well as high microgel antifouling properties. These results show the reliability of microgels assay to detect miRNAs in real samples.


Smoking ban policies in Italy and the potential impact of the so-called Sirchia Law: state of the art after eight years.
The aim of the present work is to describe the state of the art of tobacco habits in Italy, eight years after the law was introduced. Time series analyses, based on estimates of smoking prevalence/consumption derived from the openly available data of national surveys performed during the 2001-2013 period, were performed. Data have been expressed in percentage of smokers and daily cigarettes consumption. Time changes are expressed as expected annual percentage change (EAPC). Over time, the percentage of Italian smokers shows a constant and statistically significant decrease (from 28.9% in 2001 to 20.6% in 2013, EAPC = -2.6%, and P < 0.001). Regarding data stratified by gender, we found a stronger reduction among men (EAPC = -2.9%, P < 0.001) than in women (EAPC = -2.5%, P < 0.001). Similarly, the consumption of tobacco smoking, measured as the number of daily cigarettes smoked, registered a downward trend (P < 0.001). No join point (time point when a significant trend change is detected) resulted from the trend analysis. Data show a constant decrease of tobacco consumption in Italy, with no join point related to the introduction of the banning law. These findings require to reflect on the priorities of the smoking banning policies that may be focused on other intervention activities such as to increase the price of cigarettes.


Measuring the Complex Effects of the Single-Stranded DNA-Binding Protein gp2.5 on Primer Synthesis and Extension by the Bacteriophage T7 Replisome.
The single-stranded DNA-binding protein gp2.5 of bacteriophage T7 plays myriad functions in the replication of phage genomes. In addition to interacting with ssDNA, gp2.5 binds to the T7 DNA polymerase and primase/helicase proteins, regulating their enzymatic activities. Here we describe in vitro methods to examine the effects of gp2.5 on primer synthesis and extension by the T7 replisome.


Non-invasive and micro-destructive investigation of the Domus Aurea wall painting decorations.
The paper reports on the exploitation of an educated multi-technique analytical approach based on a wide non invasive step followed by a focused micro-destructive step, aimed at the minimally invasive identification of the pigments decorating the ceiling of the Gilded Vault of the Domus Aurea in Rome. The combination of elemental analysis with molecular characterization provided by X-ray fluorescence and UV-vis spectroscopies, respectively, allowed for the in situ non-invasive identification of a remarkable number of pigments, namely Egyptian blue, green earth, cinnabar, red ochre and an anthraquinonic lake. The study was completed with the Raman analysis of two bulk samples, in particular, SERS measurements allowed for the speciation of the anthraquinonic pigment. Elemental mapping by scanning electron microscopy-energy dispersive spectrometer combined with micro-fluorimetry on cross-section gave an insight into both the distribution of different blend of pigments and on the nature of the inorganic support of the red dye.


Preceptors' considerations when entrusting professional activities to postgraduate nursing students: A qualitative study.
Nurse-preceptors regularly struggle to evaluate students' readiness to take care of patients unsupervised, even with sophisticated workplace-based assessment tools. Preceptors' gut feelings are not always captured well, but are critical for judgement of readiness for learner entrustment with care tasks. Studies in medical education report features that clinicians consider important when trusting students with clinical responsibilities that might also apply in nursing. To unravel preceptors' considerations when entrusting professional activities to postgraduate nursing students. The findings may contribute to the improvement of workplace-based assessments and the training of preceptors. Thematic analysis of semi-structured interviews with sixteen nurse-preceptors from three postgraduate nursing specialisations in Dutch hospitals. Three themes emerged: CONCLUSIONS: For preceptors of postgraduate nursing students, entrustment requires more than merely insight into objectively measurable competencies. Entrusting is accompanied by subjectivity related to what preceptors expected of students. These expectations are in line with suggested factors in the literature-capability, integrity, reliability, agency, and humility-considered before entrusting students with clinical responsibilities identified in medical training. Entrusting is also accompanied by what preceptors realise about their own role in entrustment decisions. Combining different information sources made assessment more transparent and the implicit more explicit.


Sulfate and glucosamine labelling of the intercellular matrix in vitellogenic follicels of a moth.
InHyalophora cecropia the intercellular spaces of the follicles contain during vitellogenesis a matrix that can be labelled eitherin situ or in culture with35S-sulfate and3H-glucosamine. The matrix was demonstrated by autoradiography and also by treating follicles for 15 min with pronase, which released TCA-soluble matrix fragments with molecular weights of up to 2×106 daltons. Testicular hyaluronidase degraded the high molecular weight fragments, and thus it is probable that they are chondroitin sulfate-like mucopolysaccharides. With the termination of vitellogenesis new matrix is no longer deposited, and the pre-existing material is disassembled. The sulfated matrix may account for the patency of the intercellular diffusion channels essential for blood protein uptake and also for the low level, extracellular binding of blood proteins that characterizes the vitellogenic follicle inHyalophora.


Overexpression of PIM-1 is a potential biomarker in prostate carcinoma.
Prostate carcinoma (CaP) is the frequently diagnosed cancer in man. Prostate specific antigen (PSA), which is now widely used as a diagnostic marker for CaP, lacks specificity and fails to predict possible CaP progression. So it is necessary to identify the new biomarkers for CaP. We identified several genes that were differentially expressed between benign prostatic hyperplasia and CaP by microarray analysis. One gene that was overexpressed encoded a serine/threonine kinase PIM-1. Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical analysis were used to investigate PIM-1 mRNA and protein expression in malignant and benign prostate samples. PIM-1 was overexpressed in CaP, and the overexpression of PIM-1 was related to the grade and neoplastic transformation of CaP. The data, together with the molecular functions of PIM-1 suggest that PIM-1 may have an important role in CaP progression and has potential to be a diagnostic and prognostic marker for CaP.


Bis(5-amino-3-carb-oxy-1H-1,2,4-triazol-4-ium) sulfate dihydrate.
The crystal structure of the title compound, 2C(3)H(5)N(4)O(2) (+)·SO(4) (2-)·2H(2)O, displays a three-dimensional framework in which mixed infinite chains [oriented parallel to (510) and ([Formula: see text]10)] inter-fere, forming tunnels extending parallel to the c axis. Inter-molecular O-H⋯O, N-H⋯O and O-H⋯N hydrogen bonds ensure the unity of the structure and generate centrosymmetric R(4) (4)(14) and R(4) (2)(8) rings. The S atom lies on a twofold axis.


Mechanism and Prevention of Atrial Remodeling and Their Related Genes in Cardiovascular Disorders.
Atrial fibrillation (AF) is associated with profound structural and functional changes in the atrium. Inflammation mediated atrial fibrosis is one of the key mechanisms in the pathogenesis of AF. The collagen deposition in extracellular matrix (ECM) is mainly mediated by transforming growth factor β1 (TGF-β1) which promotes AF via controlling smads mediated-collagen gene transcription and regulating the balance of metalloproteinases (MMPs)/ tissue inhibitor of metalloproteinases (TIMPs). Although many processes can alter atrial properties and promote AF, animal models and clinical studies have provided insights into 2 major forms of atrial remodeling: Atrial tachycardia remodeling (ATR), which occurs with rapid atrial tachyarrhythmia's such as AF and atrial flutter, and atrial structural remodeling (ASR), which is associated with CHF and other fibrosis-promoting conditions. The mechanism of atrial remodeling such as atrial enlargement, ultra-structural changes of atrial muscle tissue and myocardial interstitial fibrosis in AF is still unclear. At present, many studies focus on calcium overload, renin angiotensin aldosterone system and transforming growth factor β1, that effect on atrial structural remodeling. Recent experimental studies and clinical investigations have provided structural remodeling is important contributor to the AF. This paper reviews the current understanding of the progresses about mechanism of atrial structural remodeling, and highlights the potential therapeutic approaches aimed at attenuating structural remodeling to prevent AF. Now some recent advancements of this area are reviewed in this paper.


Dopamine D2 receptor antagonist modulates rTMS-induced pain experiences and corticospinal excitability dependent on stimulation targets.
Both the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) rTMS have the potential to reduce certain chronic pain conditions. However, the analgesic mechanisms remain unclear, in which M1- and DLPFC-rTMS may have different impact on the release of dopamine receptor D2 neurotransmissions (DRD2). Using a double-blind, randomised, sham- and placebo-controlled design, this study investigated the influence of DRD2 antagonist on rTMS-induced analgesia and corticospinal excitability across the M1 and DLPFC. Healthy participants in each group (M1, DLPFC, or Sham) received an oral dose of chlorpromazine or placebo before the delivery of rTMS in two separate sessions. Heat pain and cortical excitability were assessed before drug administration and after rTMS intervention. DRD2 antagonist selectively abolished the increased heat pain threshold induced by DLPFC stimulation and increased pain unpleasantness. The absence of analgesic effects in DLPFC stimulation was not accompanied by plastic changes in the corticospinal pathway. In contrast, DRD2 antagonist increased corticospinal excitability and rebalanced excitation-inhibition relationship following motor cortex stimulation, although there were no clear changes in pain experiences. These novel findings together highlight the influence of dopaminergic neurotransmission on rTMS-induced analgesia and corticospinal excitability dependent on stimulation targets.


Politics in Transitional Spaces: Direct and Indirect Political Participation.
This paper seeks to build on Carriere's (2022) work on the complex, pervasive, and dialogical nature of politics and extend this treatment to examine the politics of the transitional, liminal, and "in-between spaces." In particular, we analyze the theatrical nature of politics by examining how roads and streets become a "dynamic stage" (Valsiner, 2004, p. 2) where private and public policies enter into dynamic dialogical relationships. We distinguish between direct, direct but distanced, and indirect peripheral political participation and explore how roads and streets enable redundant and dramatic communicative processes that feed into the internalization/externalization meaning-making processes (Valsiner, 2014). Finally, we analyze the process of the emergence of roads and streets as a result of complex interactions between public policies, ordinances, and values. We extend this exploration to an illustrative case in Oahu, Hawai'i to demonstrate how streets become constructed and organized to provide affective guidance. We conclude by arguing that the absence of political messages or overt political actions does not mean the absence of politics - power dynamics are still at play in the liminal and transitional zones of human living.


Rate limiting processes in the Bohr shift in human red cells.
1. The rates of the Bohr shift of human red cells and some of its constituent reactions have been studied with a modified Hartridge-Roughton rapid reaction apparatus using an oxygen electrode to measure the progress of the reaction.2. The rate of the Bohr shift was compatible with the hypothesis that the transfer of H(+) across the membrane by means of CO(2) exchange and reaction with buffers is generally the rate-limiting step.(a) When the Bohr off-reaction was produced by a marked increase in P(CO2) around the cells, the half-time at 37 degrees C was 0.12 sec. In this case CO(2) was available initially to diffuse into the cells, the process being predominantly limited by the rate of intracellular CO(2) hydration.(b) When the Bohr off-shift was produced by an increase of [H(+)] outside the cell, P(CO2) being low and equal within and outside the cells, the half time became 0.31 sec. In this case, even at the start, the H(2)CO(3) formed by the almost instantaneous neutralization reaction of H(+) and HCO(3) (-) had to dehydrate to form CO(2) and this in turn had to diffuse into and react within the red cell before the [HbO(2)] could change. When a carbonic anhydrase inhibitor was added to slow the CO(2) reaction inside the cell, the half-time rose to 10 sec.(c) The Bohr off-shift in a haemolysed cell suspension produced by an increase in P(CO2) appeared to be limited by the rate at which the CO(2) could hydrate to form H(+).3. The Bohr off-shift has an average Q(10) of 2.5 between 42.5 and 28 degrees C with an activation energy of 8000 cal.4. The pronounced importance of the CO(2)-bicarbonate system for rapid intracellular pH changes is discussed in connexion with some physiological situations.


Motif lengths of circular codes in coding sequences.
Protein synthesis is a crucial process in any cell. Translation, in which mRNA is translated into proteins, can lead to several errors, notably frame shifts where the ribosome accidentally skips or re-reads one or more nucleotides. So-called circular codes are capable of discovering frame shifts and their codons can be found disproportionately often in coding sequences. Here, we analyzed motifs of circular codes, i.e. sequences only containing codons of circular codes, in biological and artificial sequences. The lengths of these motifs were compared to a statistical model in order to elucidate if coding sequences contain significantly longer motifs than non-coding sequences. Our findings show that coding sequences indeed show on average greater motif lengths than expected by chance. On the other hand, the motifs are too short for a possible frame shift recognition to take place within an entire coding sequence. This suggests that as much as circular codes might have been used in ancient life forms in order to prevent frame shift errors, it remains to be seen whether they are still functional in current organisms.


Impact of psychiatric diagnoses on hospital length of stay in children with sickle cell anemia.
Patients with sickle cell anemia (SCA) experience a broad range of psychiatric disorders, placing them at risk for more complicated and longer hospitalizations for vaso-occlusive crises (VOC). The current study examined the frequency of psychiatric disorders in SCA patients (ages birth to 20 years) admitted for VOC in a nationally representative sample and the association between psychiatric disorders and hospital length of stay (LOS). Patients with a primary diagnosis of SCA with crisis identified through the nationally representative Kids' Inpatient Database (KID) 2006 from the Agency of Healthcare Research and Quality were included for analysis. Patients with psychiatric disorders listed as secondary diagnoses were categorized under specific psychiatric disorders (mood disorder, anxiety disorder, disruptive behavior disorder, substance use disorder). Non-parametric and regression analyses were utilized for nationally weighted data, to determine the effect of psychiatric disorders on LOS, while controlling for significant covariates. For 21,255 hospital discharges for children with SCA with crisis in 2006, the mean LOS was 4.51 days. Approximately 6% of the patients discharged had a psychiatric disorder. After adjusting for significant covariates, mood disorders, anxiety disorders, and any psychiatric disorder were each associated with significantly longer LOS (P < 0.01). Substance and disruptive behavior disorders were not associated with LOS. Pediatric patients diagnosed with a psychiatric disorder, specifically mood or anxiety disorders, have longer LOS for VOC. These findings suggest that future interventions aimed at managing VOC may need to consider adjunctive psychiatric assessment and intervention.


Update on protein structure prediction: results of the 1995 IRBM workshop.
Computational tools for protein structure prediction are of great interest to molecular, structural and theoretical biologists due to a rapidly increasing number of protein sequences with no known structure. In October 1995, a workshop was held at IRBM to predict as much as possible about a number of proteins of biological interest using ab initio prediction of fold recognition methods. 112 protein sequences were collected via an open invitation for target submissions. 17 were selected for prediction during the workshop and for 11 of these a prediction of some reliability could be made. We believe that this was a worthwhile experiment showing that the use of a range of independent prediction methods and thorough use of existing databases can lead to credible and useful ab initio structure predictions.


Influencing mechanism of temperature on the degradation of nitrobenzene in aqueous solution by ceramic honeycomb catalytic ozonation.
The heterogeneous catalytic ozonation of nitrobenzene in aqueous solution has been carried out at different reaction temperatures in a semi-continuous batch reactor where ceramic honeycomb has been used as a catalyst. The experimental results indicated that the presence of ceramic honeycomb catalyst significantly improved the degradation efficiency of nitrobenzene compared to the results from non-catalytic ozonation, and the adsorption of nitrobenzene on the catalytic surface has no significant effect on its degradation efficiency. The degradation of nitrobenzene followed the pseudo-first-order kinetic model in both the processes of ozone alone and ozone/ceramic honeycomb. With the increase of reaction temperature from 278K to 328K, the degradation efficiency of nitrobenzene, the reaction rate constants, the utilization efficiency of ozone, the formation of hydroxyl radicals (*OH) and the removal of total organic carbon (TOC) all increased in the process of ozone/ceramic honeycomb. The enhancement of reaction rate constant and the enhancement of *OH formation exhibited a good correlation in the reaction temperature scope of 278-328K.


Pharmacological characterization of the receptor involved in chemoexcitation induced by adenosine.
Experiments were performed on cats anaesthetized with pentobarbitone in which carotid body chemoreceptor activity was recorded from the peripheral end of a sectioned carotid nerve. Intracarotid (i.c.) injections of adenosine and its analogues, NECA (5'-N-ethylcarboxamidoadenosine), L-PIA(L-N6-phenylisopropyladenosine), and D-PIA(D-N6-phenylisopropyladenosine), caused dose-related increases in chemosensory discharge. The rank order of potency as chemoreceptor stimulants was: NECA greater than adenosine greater than L-PIA greater than D-PIA. Infusion of theophylline antagonized the chemoexcitatory effects of NECA, and infusion of 8-phenyltheophylline (8-PT), which is a more potent adenosine antagonist with less activity as a phosphodiesterase inhibitor, reduced the chemoexcitation induced by adenosine. Infusion of 8-PT (10 micrograms min-1 i.c.), a dose which substantially reduced the effect of injected adenosine, also reduced the sensitivity of carotid chemoreceptors to hypoxia (10% O2 for 4 min). It is concluded that the adenosine receptors in the cat carotid body which mediate chemosensory excitation are xanthine-sensitive and appear to be of the A2 sub-type. Adenosine, released within the carotid body by physiological stimuli, may be involved in chemoexcitation.


A simple and safe method for management of lymphocele after renal transplantation.
Povidone-iodine instillation into the lymphatic cavity is a simple method for lymphocele treatment in renal transplantation. We describe 2 cases successfully treated with this procedure.


Biodiversity, food, and cultureEating to Extinction Dan Saladino Farrar, Straus and Giroux, 2022. 464 pp.
A loss to one is a loss to all.


The challenges of becoming and being a clinician manager: a qualitative exploration of the perception of medical doctors in senior leadership roles at a large Australian health service.
In Australia, activity-based funding models have emphasized the need for hospitals to be accountable for their clinical performance. Clinician managers, with medical backgrounds are essential to ensuring high quality clinical performance and operational management of hospital services. The purpose of this study is to 1. Identify factors influencing doctors to become clinician managers in the Australian healthcare setting. 2. Understand the pathways and challenges faced by doctors in becoming clinician managers. We undertook a qualitative study with semi-structured interviews of 18 clinician managers (who have medical practitioner backgrounds) with formal leadership administrative roles. Interview transcripts were analysed with systematic text condensation. All eligible participants approached in this context, agreed to participate and over 80% of the participants were male. We identified five themes: 'Motivations for leadership', 'Pathways to managerial role', 'Challenges faced in management roles', 'Credibility through clinical practice' and 'Management skill cultivation and support'. Clinician managers progressed from being doctors to leadership roles through being encouraged to take on roles, while others felt pressure to take on leadership roles even if this was not a personal goal. Clinician managers described challenges such as feeling under-prepared, maintaining respect form colleagues through still participating in a clinical load, along with juggling priorities such as administrative tasks, managing budgets and performance managing other doctors. There needs to be an intentional and more structured approach to training and supporting clinician managers that considers the complex challenges faced by individuals (especially women) as they progress into these roles in the Australian tertiary health services context. There is a need to consider ways of supporting clinician managers to focus on management skills, effective mentorship and address perceptions around losing respect from colleagues if clinician managers cease their clinical loads. Further research is needed among the female medical workforce, along with research to understand if maintaining clinical loads when undertaking a clinical management role in fact leads to better effectiveness in contributing to better patient safety and quality outcomes. Such evidence may assist in addressing these social pressures among clinician managers, and contribute to addressing gender inequality among the clinical management workforce.


Clinical management of conduction abnormalities following transcatheter aortic valve replacement: prospective evaluation of a standardized management pathway.
Limited evidence guides management of conduction abnormalities following TAVR. Standardized clinical pathways may reduce variability in care while minimizing bradyarrhythmic morbidity, length of stay (LOS), and pacemaker (PPM) implantation rates. A multidisciplinary consensus pathway to standardize post-TAVR management was developed. We evaluated (1) pathway adherence; (2) LOS; (3) PPM implantation rates; (4) 1-month survival, and (5) late heart block. Exploratory analyses evaluated factors associated with PPM implantation. A total of 181 consecutive patients without prior PPM who underwent TAVR between February 2020 and February 2021 (mean age 77.9 ± 9.1, 38% women) were included. Average LOS was 3.0 days (± 2.7), and no deaths related to syncope/bradyarrhythmia were reported by 1 month. Overall, 93% of the 181 patients were managed by pathway; deviations were due to failure of discharge with a heart monitor when it was clinically indicated for either pre-existing RBBB or new PR prolongation/new LBBB. PPM implantation occurred in 19 patients by discharge, and 21 by 1-month (13%). In our exploratory analysis, pre-existing RBBB, transient peri-procedural heart block, and LOTUS valves were associated with pacemaker implantation: OR (CI) of 8.16 (3.06-21.78), 6.83 (1.94-24.03), and 8.32 (1.11-62.49), respectively. This report illustrates that a standardized protocol for the management of conduction abnormalities after TAVR can be implemented with high compliance, safe management of conduction disturbance, and relatively short LOS with discharge supported by ambulatory monitoring.


Substitutes for endangered medicinal animal horns and shells exposed by antithrombotic and anticoagulation effects.
Cornu Saigae Tataricae (antelope horn), Manis Squama (pangolin scale), Cornu Cervi Pantotrichum (velvet antler) and Cornu Bovis grunniens (yak horn) are valuable medicinal animal horns and shells (MAHS). As the major source of biological agents and ethnodrugs, MAHS show pretty good bioactivities. However, with the increased demand for MAHS, some of the medicinal resources are endangered, and there has been a concomitant increase in the prevalence of adulterated or impostor MAHS. It is of great significance to exploit the substitutes for endangered medicinal animal resources. This study is going to provide a new mode for the exploitation of the substitutes of MAHS. Plasma recalcification time, thrombin time and thrombin consumption were recorded to evaluate the anticoagulation effect of MAHS. Dissolution rate of thrombus in vitro and whole blood-gore were observed to appraise the antithrombotic effect of MAHS. All the MAHS involved in this study except Cornu Procaprae Gutturosae (argali horn), Cornu Saigae Tataricae and Cornu Bovis (cattle horn) could not only prolong recalcification time (P<0.01) and thrombin time (P<0.01), but also dissolve the thrombus in vitro (P<0.01) and whole blood-gore (P<0.01). The bioactivities among MAHS differed greatly from each other. The results indicate that Cornu Caprae Hircus (goat horn), Cornu Bubali (water buffalo horn) and Trionycis Carapax (turtle shell) are rational to be explored as the substitutes of Cornu Saigae Tataricae, Cornu Bovis grunniens and Manis Squama, respectively. On the contrary, velvet antler is not suitable to be substituted by Cornu Cervi (deerhorn). We presume that the bioactive evaluation methods are effective means of seeking substitutive resources of endangered medicinal animals with the advantages of close correlation to drug action, low dosage, and high sensitiveness.


Fas stimulation results in selective islet infiltrate apoptosis in situ and reversal of diabetes.
Breakdown of peripheral T cell regulation due to defective antigen-activated apoptosis may lead to autoimmunity. In the nonobese diabetic (NOD) mouse model of type 1 diabetes mellitus, we have demonstrated defects in T cell activation and peripheral apoptosis. Stimulation of the Fas pathway by a Fas receptor agonist led to enhanced in vitro apoptosis and in vivo selective apoptosis of islet-infiltrating lymphocytes. Administration of the Fas agonist immediately after onset of diabetes led to reversal of diabetes in NOD mice. Inducing peripheral T cell apoptosis may be a potential method for reversal of autoimmune diabetes.


Amphetamine enhances human-memory consolidation.
Although it is generally accepted that CNS stimulants have enhancing effects on long-term storage processes in laboratory animals, little is known about their influence on human learning. We report a series of experiments with free recall of lists of unrelated words, demonstrating a significant enhancement on long-term retention after amphetamine administration. A gradual increase of recall was observed up to 1 h after learning, remaining stable for at least 3 days, after oral administration before learning as well as intramuscular injection after learning. The results show that research on humans with drug-induced memory-enhancement techniques is necessary to supplement the animal studies for the understanding of the mechanisms involved in information consolidation.


Exploring time of death from potassium, sodium, chloride, glucose & calcium analysis of postmortem synovial fluid in semi arid climate.
Estimation of time of death (TOD) with fair accuracy from postmortem changes still remains an important but difficult task to be performed by every autopsy surgeon under different climatic conditions. The environment plays an important role in the process of decomposition and thereby affecting the levels of electrolytes and other biochemical parameters in the postmortem samples. Since, there is limited information available on the levels of these biochemical parameters from semi arid environment, the present study was aimed to explore time of death by analyzing electrolyte, glucose and calcium levels of postmortem synovial fluid collected from samples under such climatic conditions. The synovial fluid samples from two hundred and ten bodies brought to University College of Medical Sciences and associated Guru Teg Bahadur Hospital Delhi for medico-legal postmortem examination, during the period of November 2010 to April 2012, were analyzed for potassium, sodium, chloride, glucose and calcium. Univariate regression analysis of electrolyte concentrations of synovial fluid showed significant positive relationship between time of death and potassium (r = 0.840, p = 0.000). However, there was negative relationship between time of death and sodium (r = -0.175, p = 0.011) & glucose (r = -0.427, p = 0.000) and no significant relationship was found between time of death and calcium (r = 0.099, p = 0.152) & chloride (r = 0.082, p = 0.24) among the samples analyzed.


Application of Tandem Dispersive Liquid-Liquid Microextraction as an Efficient Method for Preconcentration of Two Antidepressant Drugs in Real Samples Combined with High Performance Liquid Chromatography.
In the present work, tandem dispersive liquid-liquid microextraction (TDLLME) coupled with liquid chromatography was used for the determination of the two antidepressant drugs citalopram (CIT) and sertraline (SER) in complicated matrices. Indeed, the present approach was used to improve the suitability and appropriateness of the dispersive liquid-liquid microextraction (DLLME) method in complicated matrices. Firstly, 10 mL of the sample solution containing the two understudied drugs was extracted into an organic solvent (200 μL of 1,2-dichloromethane) using the DLLME method. Then the extracted analytes were back-extracted into 100 μL of an aqueous acceptor phase. The total extraction time of this method is about 6 min. To achieve the best efficiency for this method, efficient parameters like the kind and volume of the organic solvent and the effect of the ionic strength on the effectiveness of extraction were reviewed and improved. Under the optimized experimental conditions, TDLLME showed good linearity in the range of 100.0-7000.0 ng mL-1. The limits of detection were found to be 10.0 ng mL-1 for CIT and 2.0 ng mL-1 for SER. The relative standard deviation (RSD) is obtained in the range of 0.7-4.1%.


Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study.
It has been suggested that oxidative stress and mitochondrial DNA damage play important roles in breast cancer carcinogenesis. Manganese superoxide dismutase (MnSOD) is a major enzyme that is responsible for the detoxification of reactive oxygen species in the mitochondria. A T --> C substitution in the MnSOD gene results in a Val --> Ala change at the -9 position of the mitochondrial targeting sequence (Val-9Ala), which alters the protein secondary structure and thus affects transport of MnSOD into the mitochondria. We evaluated this genetic polymorphism in association with breast cancer risk using data from the Shanghai Breast Cancer Study, a population-based case-control study conducted in urban Shanghai from 1996 to 1998. The MnSOD Val-9Ala polymorphism was examined in 1125 breast cancer cases and 1197 age-frequency-matched control individual. Breast cancer risk was slightly elevated in women with Ala/Ala genotype (odds ratio [OR] 1.3, 95% confidence interval [CI] 0.7-2.3), particularly among premenopausal women (OR 1.8, 95% CI 0.9-3.7), as compared with those with Val/Val genotype. The increased risk with the Ala/Ala genotype was stronger among premenopausal women with a higher body mass index (OR 2.5, 95% CI 0.9-7.0) and more years of menstruation (OR 2.6, 95% CI 0.8-8.0). The risk among premenopausal women was further increased twofold to threefold among those with a low intake of fruits, vegetables, vitamin supplements, selenium, or antioxidant vitamins, including carotenes and vitamins A, C, and E. However, the frequency of the Ala allele was low (14%) in the study population, and most of the ORs provided above were not statistically significant. The present study provides some evidence that genetic polymorphism in the MnSOD gene may be associated with increased risk of breast cancer among Chinese women with high levels of oxidative stress or low intake of antioxidants. Studies with a larger sample size are needed to confirm the findings.


Biofeedback, voluntary control, and human potential.
This paper examines some of the philosophical and scientific relationships involving self-control, voluntary control, and psychophysiologic self-regulation. The role of biofeedback in mediating conscious and unconscious processes is explored. Demonstrations of superior voluntary control and its relationship to belief, confidence, and expectation are examined. Biofeedback demonstrates the potential of control to oneself, creating confidence in one's ability to establish enhanced and peak performance in athletics, education, and psychophysiologic therapy. Emphasis is placed on the power of images in all human functioning, and in enhancing human potential.


Personality Traits are Related to Selective Cognitive Impairment in Early Alzheimer's Disease.
A link between personality traits and cognitive performance has been shown in normal adults and elderly individuals. Very few studies have evaluated this link in Alzheimer's disease (AD). To better understand cognitive performance as regards to personality traits, our study was aimed to evaluate the role of premorbid personality on cognitive functioning in a population of patients presenting prodromal or mild AD. 181 elderly with prodromal or mild AD participated in a cross-sectional, prospective cohort study. The participants completed a personality inventory and a neuropsychological battery exploring memory, attention, executive function, language, and praxis. Cognitive performance were compared according to the level of each personality trait, using multivariate MANOVA models. A higher level of neuroticism was associated with lower performance at similarities test (D = 9.49, p = 0.003), delayed Free and Cued Selective Reminding test (D = 5.22, p = 0.02), and digit span score (D = 7.99, p = 0.006). A higher level of openness was related to better performance at similarities (D = 4.33, p = 0.04), letter fluency (D = 11.45, p = 0.001), and category fluency test (D = 5.85, p = 0.02). Neuroticism interfered negatively with cognitive functioning at the prodromal stage; the association between openness and cognitive function was observed at both prodromal and mild AD stage. These results suggest that personality traits, in particular neuroticism and openness, modulate cognitive abilities in patients with early AD. These results encourage the development of stress management programs to prevent its negative effects on cognitive aging.


Healthcare providers' acceptance of telemedicine and preference of modalities during COVID-19 pandemics in a low-resource setting: An extended UTAUT model.
In almost all lower and lower middle-income countries, the healthcare system is structured in the customary model of in-person or face to face model of care. With the current global COVID-19 pandemics, the usual health care service has been significantly altered in many aspects. Given the fragile health system and high number of immunocompromised populations in lower and lower-middle income countries, the economic impacts of COVID-19 are anticipated to be worse. In such scenarios, technological solutions like, Telemedicine which is defined as the delivery of healthcare service remotely using telecommunication technologies for exchange of medical information, diagnosis, consultation and treatment is critical. The aim of this study was to assess healthcare providers' acceptance and preferred modality of telemedicine and factors thereof among health professionals working in Ethiopia. A multi-centric online survey was conducted via social media platforms such as telegram channels, Facebook groups/pages and email during Jul 1- Sep 21, 2020. The questionnaire was adopted from previously validated model in low income setting. Internal consistency of items was assessed using Cronbach alpha (α), composite reliability (CR) and average variance extracted (AVE) to evaluate both discriminant and convergent validity of constructs. The extent of relationship among variables were evaluated by Structural equation modeling (SEM) using SPSS Amos version 23. From the expected 423 responses, 319 (75.4%) participants responded to the survey questionnaire during the data collection period. The majority of participants were male (78.1%), age <30 (76.8%) and had less than five years of work experience (78.1%). The structural model result confirmed the hypothesis "self-efficacy has a significant positive effect on effort expectancy" with a standardized coefficient estimate (β) of 0.76 and p-value <0.001. The result also indicated that self-efficacy, effort expectancy, performance expectancy, facilitating conditions and social influence have a significant direct effect on user's attitude toward using telemedicine. User's behavioral intention to use telemedicine was also influenced by effort expectancy and attitude. The model also ruled out that performance expectancy, facilitating conditions and social influence does not directly influence user's intention to use telemedicine. The squared multiple correlations (r2) value indicated that 57.1% of the variance in attitude toward using telemedicine and 63.6% of the variance in behavioral intention to use telemedicine is explained by the current structural model. This study found that effort expectancy and attitude were significantly predictors of healthcare professionals' acceptance of telemedicine. Attitude toward using telemedicine systems was also highly influenced by performance expectancy, self-efficacy and facilitating conditions. effort expectancy and attitude were also significant mediators in predicting users' acceptance of telemedicine. In addition, mHealth approach was the most preferred modality of telemedicine and this opens an opportunity to integrate telemedicine systems in the health system during and post pandemic health services in low-income countries.


Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators.
GS-9688 (selgantolimod) is a toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS-9688 has previously been evaluated in vitro in HBV-infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS-9688 to boost responses contributing to viral control and to modulate regulatory mediators. We characterized the effect of GS-9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS-9688 activated dendritic cells and mononuclear phagocytes to produce IL-12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS-9688 increased the frequency of activated natural killer (NK) cells, mucosal-associated invariant T cells, CD4+ follicular helper T cells, and, in about 50% of patients, HBV-specific CD8+ T cells expressing interferon-γ. Moreover, in vitro stimulation with GS-9688 induced NK-cell expression of interferon-γ and TNF-α, and promoted hepatocyte lysis. We also assessed whether GS-9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS-9688 reduced the frequency of CD4+ regulatory T cells and monocytic myeloid-derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin-9 and programmed death-ligand 1. Conversely, GS-9688 induced an expansion of immunoregulatory TNF-related apoptosis-inducing ligand+ NK cells and degranulation of arginase-I+ polymorphonuclear MDSCs. GS-9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV-specific CD8+ T cells, CD4+ follicular helper T cells, NK cells, and mucosal-associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS-9688.


A prospective comparison of bone-patellar tendon-bone and hamstring grafts for anterior cruciate ligament reconstruction in female patients.
The aim of the study is to compare the results after arthroscopic anterior cruciate ligament (ACL) reconstruction using central-third, bone-patellar tendon-bone (BTB group) (n = 28) and four-strand semitendinosus/gracilis (ST/G group) (n = 31) autografts in female patients. The type of study was non-randomised prospective consecutive series. A consecutive series of 61 female patients, all with unilateral ACL ruptures, was included in the study. In both groups, interference screw fixation of the graft was used at both ends, and 59/61 (97%) of the patients returned for the follow-up examination after a period of 26 (23-31) months. The pre-operative assessments in both groups were similar in terms of the Lysholm score, KT-1000 measurements, one-leg-hop test, and knee-walking test. At the 2-year follow-up, the knee-walking test was significantly worse in the BTB group than in the ST/G group (P = 0.003). Furthermore, the knee-walking test was significantly worse at follow-up than pre-operatively in the BTB group (P < 0.005). The corresponding finding was not made in the ST/G group. A reduction in knee laxity compared with the pre-operative assessments was found in both groups. No significant difference in the post-operative knee laxity measurement was found between the groups. A significant increase in activity level and subjective scores was found in both groups compared with pre-operative values, without any significant differences between the groups. Two years after ACL reconstruction, the groups displayed no significant differences in terms of functional outcome and knee laxity. However, the use of ST/G autografts rendered significantly less discomfort during the knee-walking test than the use of BTB autografts.


Broadband perovskite quantum dot spectrometer beyond human visual resolution.
The quantum dot spectrometer, fabricated by integrating different quantum dots with an image sensor to reconstruct the target spectrum from spectral-coupled measurements, is an emerging and promising hyperspectrometry technology with high resolution and a compact size. The spectral resolution and spectral range of quantum dot spectrometers have been limited by the spectral variety of the available quantum dots and the robustness of algorithmic reconstruction. Moreover, the spectrometer integration of quantum dots also suffers from inherent photoluminescence emission and poor batch-to-batch repeatability. In this work, we developed nonemissive in situ fabricated MA3Bi2X9 and Cs2SnX6 (MA = CH3NH3; X = Cl, Br, I) perovskite-quantum-dot-embedded films (PQDFs) with precisely tunable transmittance spectra for quantum dot spectrometer applications. The resulting PQDFs contain in situ fabricated perovskite nanocrystals with homogenous dispersion in a polymeric matrix, giving them advantageous features such as high transmittance efficiency and good batch-to-batch repeatability. By integrating a filter array of 361 kinds of PQDFs with a silicon-based photodetector array, we successfully demonstrated the construction of a perovskite quantum dot spectrometer combined with a compressive-sensing-based total-variation optimization algorithm. A spectral resolution of ~1.6 nm was achieved in the broadband of 250-1000 nm. The performance of the perovskite quantum dot spectrometer is well beyond that of human eyes in terms of both the spectral range and spectral resolution. This advancement will not only pave the way for using quantum dot spectrometers for practical applications but also significantly impact the development of artificial intelligence products, clinical treatment equipment, scientific instruments, etc.


Long term follow-up of a case of Kasabach-Merritt syndrome successfully treated with radiotherapy and corticosteroids.
Kasabach-Merritt syndrome is the association of thrombocytopenia, spontaneous bleeding, and enlargement of a haemangioma. It is caused by an intense, self-perpetuating process of clot-formation and lysis within the abnormal vascular channels of the haemangioma, and results in consumption of platelets and clotting factors. Treatment involves ablation of the lesion with or without pharmacological manipulation of the coagulation and fibrinolytic systems. No single therapeutic modality is universally successful but a combination of radiotherapy and corticosteroids can result in a dramatic, immediate response with minimal long term complications.


Alteration in the transmission of TSH-message to thyroid target in a transplantable rat thyroid tumor.
Plasma membranes derived from a transplantable rat thyroid tumor (line 1-5G in Wollman's classification), which is unresponsive to thyrotropin (TSH) but is responsive to dibutyryl 3', 5' cAMP, have been evaluated to localize the defect. TSH binding in tumor plasma membrane is slightly lower than in normal rat thyroid membranes. No change in affinity, but simply a lower capacity was observed. The glycoprotein component of the TSH receptor exhibits similar binding and solubilization properties to the glycoprotein component derived from normal rat thyroid. Analogously to normal rat thyroid membranes, gangliosides more complex than N-acetylneuraminylgalactosylglucosyl-ceramide (GM3) are also present in tumor line 1-5G membranes. Phospholipid content of tumor line 1-5G is 50% lower than that of normal rat thyroid. At variance also with normal rat thyroid, 32P incorporation in tumor line 1-5G phospholipids such as phosphatidylserine and phosphatidylethanolamine is not modified after in vitro incubation with TSH. An even more pronounced effect by TSH on 32P incorporation into phosphatidylinositol is evident in tumor line 1-5G by comparison to normal. The 1-5G thyroid tumor membranes has a 12-fold higher basal adenylate cyclase activity than that of rat thyroid membranes. The high basal adenylate cyclase activity is associated with high ADP ribosylation activity. Both enzymes of tumor are only slightly responsive to TSH. These results suggest that the block in the transmission of TSH message to the cell machinery is localized to the regulatory domains between TSH receptor and adenylate cyclase catalytic subunit.


Transesophageal echocardiography during repair of congenital cardiac defects: identification of residual problems necessitating reoperation.
One advantage of intraoperative transesophageal echocardiographic (TEE) evaluation during surgery for congenital heart disease is detection of suboptimal repairs, thus providing the opportunity to return to cardiopulmonary bypass (CPB) to repair residual defects. The purpose of this study was to evaluate the impact of TEE on decisions to return to CPB. Two-hundred-thirty infants and children with a variety of defects were studied with size-appropriate TEE probes. Patients were grouped by anatomic defect or surgical procedure for which TEE was requested. After CPB, pre- and post-CPB TEE anatomic, functional, and flow evaluations were compared. TEE findings prompted a return to CPB to repair residual defects in 17 of 230 (7.4%) patients. By diagnosis, return to CPB occurred in 9 of 28 (32%) patients with left ventricular outflow tract obstruction, 5 of 78 (6.4%) patients with ventricular septal defect, 1 of 16 (6%) patients with switch-repaired transposition, 1 of 32 (3%) with aortic valve disease, and 1 of 3 with double outlet right ventricle. All post-CPB diagnoses were confirmed during reoperation. Although post-CPB TEE provided reassuring information in patients with other diagnoses, TEE impact on return to CPB appears to be significant in a small group of primary diagnoses. The sensitivity and specificity of TEE determination of the need for reoperation were 89% and 100%, respectively. By identifying the site, severity, and mechanism of residual problems, TEE offers substantial utility in detection of residual problems in need of reoperation.


Evaluation of Tanacetum larvatum for an anti-inflammatory activity and for the protection against indomethacin-induced ulcerogenesis in rats.
Oral administration of the chloroform extract from Tanacetum larvatum (Griseb. ex Pant.) Kanitz caused a dose-dependent anti-inflammatory effect in the carrageenan-induced rat paw oedema test. The obtained anti-inflammatory effect was 8.6, 32.8, 37.0 and 49.5% for the extract doses of 25, 50, 100 and 200mg/kg, respectively, being statistically significant at a dose of 50mg/kg. Indomethacin had a strong anti-inflammatory effect of 73.4% at a dose of 8mg/kg, but large gastric lesions were detected. When the plant extract in the highest tested dose (200mg/kg) was concomitantly given with indomethacin, the anti-inflammatory effect was slightly enhanced, but the gastric lesions were significantly reduced. The anti-inflammatory and anti-ulcer activity may be mainly due to the inhibition of DNA binding of the transcription factor NF-kappaB by components of the plant extract. This was proven in an electrophoretic mobility shift assay at a concentration of 50microg/ml. Due to its anti-inflammatory as well as anti-ulcer effects, Tanacetum larvatum should especially be used combined with those drugs that are known both for their strong anti-inflammatory activities and the ulcerogenic side effects such as NSAIDs.


Development of intracardiac thrombus in a young patient with antiphospholipid syndrome while she was on rivaroxaban: Case report and literature review.
The probability of right heart thrombus co-existence should be considered in patients with antiphospholipid syndrome (APS) who have pulmonary and cardiac symptoms. The prevention and management of intracardiac thrombotic events include early use of anticoagulation therapy.


Design and construction of small perturbation mutagenesis libraries for antibody affinity maturation using massive microchip-synthesized oligonucleotides.
We report a rational strategy to design and construct multiple small perturbation mutagenesis (SPM) libraries using massively parallel synthesis of oligonucleotides on a microchip for affinity maturation of an engineered anti-ErbB2 antibody chA21. On the basis of a comprehensive analysis of the sequence and structural relationships of six complementary determination regions (CDRs) in the Kabatman database, a computational algorithm was developed to introduce single-site and double-site mutations into variable CDR positions using ambiguous nucleotides. The six SPM libraries were composed of 419 degenerate oligonucleotides that can be expanded into 161,832 unique CDR sequences with a high coverage ratio of 95% natural amino acid diversity. We used Illumina next-generation sequencing to demonstrate that the synthetic CDR library sequences, as well as relative quantities per sequence, can be controlled precisely by adjusting reaction chamber assignment and input nucleoside composition. The microchip-synthesized oligonucleotides were used for construction of single-chain antibody fragment (scFv) phage libraries through one-step mutagenic PCR of double-stranded plasmids with >10(6)E. coli transformants. A variant with combinatorial mutations from four individual CDRs achieved more than 19-fold affinity increase. The strategy described herein should be broadly applicable to affinity and selectivity studies of antibodies and other proteins.


Intrafractional monitoring of patients using four different immobilization mask systems for cranial radiotherapy.
Patients receiving cranial radiotherapy are immobilized with a thermoplastic mask to restrict patient motion. Depending on the target volume margins and treatment dose, different mask systems are used. Intrafractional movements can be monitored using stereoscopic X-ray imaging. The aim of the present work was to compare the magnitudes of intrafractional deviation for different mask systems. Four different head mask systems (open face mask, open mask, stereotactic mask, double mask) used in the treatment of 40 patients were investigated. In total 487 treatment fractions and 3708 X-ray images were collected. Deviations were calculated by comparison of the acquired X-ray images with digitally reconstructed radiographs. The results of intrafractional X-ray deviations for translational and rotational axes were compared between the different mask systems. Deviations were below 0.6 mm for translations and below 0.6° for rotations for all mask systems. Along the lateral and longitudinal directions the stereotactic mask was superior, while along the vertical direction the double mask showed the lowest deviations. For low rotational deviations the double mask is the best amongst all other mask systems. As expected, the lowest movement was shown using cranial stereotactic mask systems. The results have shown deviations lower than 0.6 mm and 0.6° using any of the four thermoplastic mask systems.


Sexual transmission of predicted CXCR4-tropic HIV-1 likely originating from the source partner's seminal cells.
We present a case of sexual transmission of HIV-1 predicted to have CXCR4-tropism during male-to-male sexual exposure. Phylogenetic analyses exclude cell-free virus in the seminal plasma of the source partner and possibly point to the seminal cells as the origin of the transmission event.


Roles of superoxide and myeloperoxidase in ascorbate oxidation in stimulated neutrophils and H2O2-treated HL60 cells.
Ascorbate is present at high concentrations in neutrophils and becomes oxidized when the cells are stimulated. We have investigated the mechanism of oxidation by studying cultured HL60 cells and isolated neutrophils. Addition of H(2)O(2) to ascorbate-loaded HL60 cells resulted in substantial oxidation of intracellular ascorbate. Oxidation was myeloperoxidase-dependent, but not attributable to hypochlorous acid, and can be explained by myeloperoxidase (MPO) exhibiting direct ascorbate peroxidase activity. When neutrophils were stimulated with phorbol myristate acetate, about 40% of their intracellular ascorbate was oxidized over 20 min. Ascorbate loss required NADPH oxidase activity but in contrast to the HL60 cells did not involve myeloperoxidase. It did not occur when exogenous H(2)O(2) was added, was not inhibited by myeloperoxidase inhibitors, and was the same for normal and myeloperoxidase-deficient cells. Neutrophil ascorbate loss was enhanced when endogenous superoxide dismutase was inhibited by cyanide or diethyldithiocarbamate and appears to be due to oxidation by superoxide. We propose that in HL60 cells, MPO-dependent ascorbate oxidation occurs because cellular ascorbate can access newly synthesized MPO before it becomes packaged in granules: a mechanism not possible in neutrophils. In neutrophils, we estimate that ascorbate is capable of competing with superoxide dismutase for a small fraction of the superoxide they generate and propose that the superoxide responsible is likely to come from previously identified sites of intracellular NADPH oxidase activity. We speculate that ascorbate might protect the neutrophil against intracellular effects of superoxide generated at these sites.


Advances in viral-vector systemic cytokine gene therapy against cancer.
Current strategies for cancer gene therapy consist mainly of direct inhibition of tumor cell growth and activation of systemic host defense mechanisms. Cytokine gene-transduced tumor cells have been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Cytokines should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression at the level of improving immune stimulation. In this review, we will summarize the current achievements of cytokine gene therapy, especially viral-vector, and their applications in cancer treatment. Additionally, we will also discuss and propose future perspectives about cancer gene therapy.


[Time-influencing factors for biochemical progression following radical prostatectomy].
We assessed the time-influencing clinical-pathological factors for biochemical progression of an equal series of patients from a single institution. Retrospective analysis of 278 patients with biochemical progression following prostatectomy. We considered biochemical progression to be PSA>0.4 ng/ml. We performed the trial using the Cox model (univariate and multivariate) and using the Student's t-test to compare averages. With a mean follow-up of 4 (±3 DE) years, the univariate study showed a mean until progression for the Gleason score 2-6 in the biopsy of 824 days and 543 for the Gleason score 7-10 (p=0.003). For negative surgical margins, the mean was 920 days and 545 for positive margins (p=0.0001). In the case of a Gleason score 2-7 in the specimen, the mean was 806 days and 501 for a Gleason score 8-10 (p=0.001). Lastly, the mean for the cases with Ki-67 negative in the specimen (< 10%) was 649 days and 345 for Ki-67 positive (> 10%) (p=0.003). In the multivariate study, Ki-67 (OR 1.028; IC 95% 1-1.01; p=0.0001) and Gleason score 8-10 (OR 1.62; IC 95% 1.5-2.45; p=0.026) in the specimen, and initial PSA >10 ng/ml (OR 1.02; IC 95% 1.01-1.04; p=0.0001) were independent variables. Using these variables, we designed a predictive model with three groups. The time until the progression of each group was 1,081, 551 and 218 days respectively. The Gleason score 7-10 in the prostate biopsy, the presence of Ki-67, the positive margins and the Gleason score 8-10 in the specimen, and the initial PSA > 10 ng/ml are time-influencing factors until biochemical progression. Pathological Gleason score 8-10, PSA > 10 ng/ml and Ki-67 are independent factors.


Impacts of freeze-thaw processes and subsequent runoff on 137Cs washoff from bare land in Fukushima.
The deposited 137Cs is one of the long-lived radionuclides, that was released following the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident, has been hydrologically transported as particulates in the terrestrial environment of the Fukushima region. The impact of freeze-thaw processes and subsequent runoff affecting the 137Cs flux and concentration in sediment discharge were revealed in bare land erosion plot following the FDNPP accident by detailed monitoring and laser scanner measurement on the soil surface. We found that surface topographic changes due to the frost-heaving during the winter-spring period, and rill formation during the summer. We also found the evident seasonal changes in 137Cs concentration; high during the early spring and gradually decreased thereafter, then surface runoff from the plot frequently occurred during spring and autumn when rainfall was high and reached a maximum in summer. From these results, the higher 137Cs concentration in spring was caused by a mixture of unstable surface sediment following freeze-thaw processes and then transported in the early spring, but erosion amount is not significant because of the less rainfall event. The sediment with a lower 137Cs concentration, which was supplied from the rill erosion and its expansion, was wash-offed during the summer, contributing most of the flux from erosion in bare land in Fukushima region. In case, heavy rainfall occurs in the early spring, caution is required because high concentrations of cesium may flow down into the river.


Antibodies against membrane interleukin 1 alpha activate accessory cells to stimulate proliferation of T lymphocytes.
Some monoclonal antibodies (mAbs) against interleukin (IL) 1 alpha have been found to activate antigen-presenting cells (APC, human peripheral blood monocytes and B lymphocytes), so that unstimulated T lymphocytes cultured with them are induced to proliferate and secrete IL-2. Control mAbs of the same isotypes and mAbs against IL-1 beta do not activate APC. In the absence of APC, mAbs against IL-1 alpha do not induce proliferation of T lymphocytes. Mitomycin C-treated activated APC still induce T-cell proliferation. Proliferation of T lymphocytes cannot be induced by culture supernatants and requires contact with APC activated by mAbs against IL-1 alpha. The observations imply that surface membrane IL-1 alpha can function as a triggering molecule on APC, which could play an important role in the initiation of immune responses by T lymphocytes.


Optical measurement platform of temperature-dependent interaction between nanoliposomes and a polymer-grafted surface.
In this study, we report an opto-microfluidic platform integrated with dark-field light scattering imaging and fluorescence microspectroscopy to investigate the temperature-dependent behavior of nanoliposomes. This newly developed experimental platform enabled both in situ measurements of the temperature of the sample solution and observation of individual nanoliposomes. As a proof-of-concept, the temperature-dependent interaction between 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) nanoliposomes and a poly(ethylene glycol) (PEG) grafted surface was investigated using this opto-microfluidic platform. Temperature-dependent detachment behavior of DLPC nanoliposomes, which was because of the phase transition of DLPC, was observed. The opto-microfluidic platform for individual nanoparticle measurements may become a powerful tool for investigating temperature-dependent physicochemical properties of nanoparticles in aqueous solution.


Surgery for rupture of extensor tendons in rheumatoid arthritis.
Forty-two patients underwent fifty-four operations for rupture of extensor tendons in rheumatoid disease. The results are analysed and factors affecting the results discussed.


Choleretic effects of yarrow (Achillea millefolium s.l.) in the isolated perfused rat liver.
Different species from the Achillea millefolium aggregate are used against gastrointestinal and hepato-biliary disorders in traditional European medicine. In this work, a fraction enriched in dicaffeoylquinic acids (DCCAs) and luteolin-7-O-beta-D-glucuronide was investigated on its choleretic effect in the isolated perfused rat liver (IPRL) compared to cynarin (1,3-DCCA), the main choleretic compound of Cynara scolymus L. A fraction containing 3,4-, 3,5- and 4,5-DCCA and luteolin-7-O-beta-D-glucuronide was prepared by solid phase extraction from a 20% methanolic extract of yarrow. A total amount of 48.8% DCCAs and 3.4% luteolin-7-O-beta-D-glucuronide was determined by HPLC analysis with cynarin as internal standard. IPRL experiments revealed a dose-dependant increase in bile flow (23-44-47%) by the Achillea fraction. Choleresis was two- to three-fold higher than that of cynarin. The combined effect of DCCAs and luteolin-7-O-beta-D-glucuronide stimulated bile flow more effectively than the single compound cynarin. Due to their polar structure, these compounds are quantitatively extracted into teas and tinctures; hence, they seem to be the choleretic active principles in the traditional application forms of yarrow.


Intron-derived microRNAs--fine tuning of gene functions.
New evidence suggests that abundant small RNAs, microRNAs (miRNAs) act as regulatory vehicles to repress translation or cleave RNA transcripts, depending on their complementarity to the target gene, and result in modulation of gene expression. This review describes that the miRNAs derived from introns can suppress intracellular RNA homologues and regulate the gene function.


Production of specific antibodies to contractile proteins, and their use in immunofluorescence microscopy. II. Species-specific and species-non-specific antibodies to smooth and striated chicken muscle actin.
The injection of rabbits with insoluble or soluble G-actin from chicken smooth or striated muscle will produce antibodies that are equally reactive, and species and tissue non-specific in immunoprecipitation, immunofluorescence and actin-activated Mg2+-ATPase inhibition tests. These antibodies have been used for the identification of actin-containing fibrils in a variety of tissues. When G-actins from chicken smooth or striated muscle are immobilized by chemical linkage to Affi-Gel 702 microbeads, their immunogenicity is increased, but the antibodies obtained against them are species-specific and will only react with actin and actin-containing structures from chicken and are therefore limited in use. It is concluded from this work that insoluble G-actin is the preferable immunogen to obtain precipitating antibodies for wide use.


Homotypic aggregates contribute to heterogeneity in B cell fates due to an intrinsic gradient of stimulant exposure.
Monocultures of several cell types result in the formation of robust clusters called homotypic aggregates (HAs). How this physical aggregation affects cell fates in immune cell cultures, is poorly understood. We studied anti-CD40-stimulated primary B cell cultures, where cells assembled into large three-dimensional LFA1-driven HAs by 72 h. The dense packing in these aggregates restricts the infiltration of stimulants, such as antibodies, to cells inside the clusters. This creates a concentration gradient of stimulant availability across the cross-section of HAs. We describe a method to retain this positional information even after the disruption of HAs, for analysis by flow cytometry. Comparison of stage-specific cell-surface markers showed that the extent of stimulant-binding affected multiple fates non-uniformly. While germinal center and lineage markers were moderately upregulated, immunoglobulins and markers associated with memory were more than doubled in the peripheral cells binding more anti-CD40. These cells also experienced a strong repression of the plasma cell regulator Prdm1 and an upregulation of the oncogene Myc. Thus, cells at different locations in HAs are subjected to unequal doses of stimulants, leading to a hitherto unreported source of heterogeneity in cell fates. These findings can be extrapolated to understand the dose-dependent effects of stimulants in other three-dimensional cell clusters.


Raynaud's phenomenon.
Raynaud's phenomenon occurs in about 5% of the adult population, and most individuals do not seek medical attention for the condition. In symptomatic patients with Raynaud's phenomenon, it is useful to categorize the condition as primary or secondary. In addition to providing a framework for epidemiologic and therapeutic protocols, such classification may reflect basic pathophysiologic differences. Occupation-related Raynaud's phenomenon has been recognized recently as a major cause of lost wages and productivity. Neurogenic and "local fault" hypotheses to explain primary Raynaud's phenomenon are still being studied. In secondary Raynaud's phenomenon, obliterative arteriopathy and the role of endothelial-derived products have been the focus of intense research interest. Under some circumstances, the combination of nailfold capillary microscopy and autoantibody analysis can identify patients with primary Raynaud's phenomenon that is likely to evolve into a secondary form of Raynaud's phenomenon. Although information from this type of analysis may be overinterpreted, the prognostic yield is highest for patients destined to develop systemic sclerosis-related disorders. Newer vasodilating agents and antithrombotic drugs may offer benefit for patients with both primary and secondary Raynaud's phenomenon.


"Then and Now," Mapping the 25 Year Evolution and Impact of North American Vascular Biology Organization Science Through Publications of its Founding and Current Members.
Scholarly organizations bring together experts to move forward specific areas of scientific endeavor. More than 5,000 scholarly societies exist world-wide yet little is known about the composition, evolution, and collaboration of experts within these organizations. This study presents general methods to study the evolution of a biomedical organization and its impact over time. Methods are illustrated in a case study that aims to capture the "Then and Now" science of the North American Vascular Biology Organization (NAVBO). Publications authored by the founding members who came together to create NAVBO in 1994 are compared with publications by those representing the society 25 years later. Google Scholar data was compiled for NAVBO members registered in 1994 (n = 70) and in 2019 (n = 465), some members being present in both data sets (n = 22). The 501 unique NAVBO members had more than 76,000 papers cited over 4,400,000 times. Several characteristics associated with the NAVBO members' output were revealed, including their high productivity, the high impact of their publications, and the predominant contribution of relatively small laboratories, as suggested by a low average number of authors per publication. To understand how NAVBO fostered scientific collaborations and exchanges of expertize, data was analyzed and visualized to show the evolution of member co-author networks. The UCSD Map of Science was used to communicate the evolution of scientific topics covered by NAVBO members helping to create a global picture of NAVBO's science "then and now." All workflows are available online in case other scholarly organizations would want to use them to map their own evolution and impact; and meta studies that communicate the inner workings of these important scholarly efforts can be conducted.


Distribution and synaptic localization of nicotinic acetylcholine receptors containing a novel alpha7 subunit isoform in embryonic rat cortical neurons.
Neuronal nicotinic acetylcholine receptors (nAChRs) containing the alpha7 subunit isoform, alpha7-2 (alpha7-2-nAChRs), have previously been found to form functional homopentameric channels that desensitize slowly and bind alpha-bungarotoxin (alphaBgt) in a rapidly reversible manner. This isoform incorporates a novel cassette exon in the extracellular, ligand binding domain of the native receptor. Although this alpha7 subunit isoform has been detected in peripheral ganglia as well as in the central nervous system, little is known about the cellular function of alpha7-2-nAChRs. Co-localization immunocytochemical studies were conducted in an embryonic rat cultured cortical neuron model using a polyclonal antibody (Ab 87) raised against the amino acid sequence of the cassette exon, in combination with (1) an antibody that recognizes all known alpha7-nAChRs, (2) alphaBgt, and (3) antibodies directed against multiple cellular markers. The pattern of alpha7-2-nAChR expression was consistent with alpha7 staining in general, based on co-distribution of mAb319 and alphaBgt signals. However, alpha7-2-nAChRs clearly represent a distinct subset of alpha7 receptors. The alpha7-2-nAChR subtype was found throughout the cell-soma surface and was localized to a subpopulation of dendrites. Punctate staining characteristic of synaptic alpha7-2 targeting was observed at post-synaptic densities and intermittently at pre-synaptic locations. The alpha7-2 subunit was expressed on both GABAergic and non-GABAergic neurons. These studies reveal that receptors containing the alpha7-2 subunit constitute a subpopulation of alpha7-nAChRs and likely participate in cell-to-cell signaling in developing synapses of central neurons.


Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis.
Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca(2+)) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca(2+) leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca(2+) leak function activity and Ca(2+) overload in the ER. These results provided potential explanation for abnormal Ca(2+) signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca(2+) leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.


Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying lipid metabolites as drivers of hepatocyte stress.
The global population of people over the age of 65 is increasing and expected to reach 1.5 billion by 2050. While aging is associated with a number of chronic illnesses including dementia, the underlying contribution of alcohol misuse in the elderly is understudied. Long-term chronic alcohol misuse can lead to alcohol-associated liver disease, consisting of a spectrum of pathologies, including steatosis and cirrhosis; liver disease can be rapidly accelerated by non-resolving inflammation. Despite this knowledge, the mechanistic underpinnings of dysregulated host immunity and accelerated liver disease progression in the aged by alcohol is unknown. Alcohol misuse in the elderly is on the rise and aging is associated with progressive increases in pro-inflammatory cytokine production. The goals of the current study are to characterize bioactive lipid mediators of inflammation by making use of a murine model of ethanol-induced liver disease in 3-month-old and 20-month-old mice by quantitatively profiling selected oxylipins in liver, brain and plasma. Following chronic ethanol exposure, liver injury, steatosis, and senescence markers were robustly increased in aged mice compared to young adult mice. Expression of proinflammatory cytokines and lipid metabolizing enzymes were increased in liver by both age and ethanol feeding. Lipoxygenase-derived lipid metabolites 9- and 13-hydroxy-octadecadienoic acid and 15-hydroxyeicosatetraenoic acid were increased in liver and plasma in ethanol-fed aged mice and positively correlated with liver injury. In plasma, 9,10-dihydroxy-octadecenoic acid/epoxy-octadecenoic acid plasma ratios correlated with liver injury in ethanol-fed aged mice. Finally, 15-hydroxyeicosatetraenoic acid and 9,10-dihydroxy-octadecenoic acid positively correlated between liver and plasma. Importantly, leukotriene E4, 9,10-dihydroxy-octadecenoic acid and 15-hydroxyeicosatetraenoic acid increased lipid accumulation and ER stress in cultured AML12 hepatocytes. These data highlight the complexity of lipid metabolite networks but identify key mediators that may be used for diagnostic and prognostic markers in early stages of alcohol-related liver disease in patients of all ages.


Studies on the metabolic defect in Broad-beta disease (hyperlipoproteinaemia type III).
The apoprotein composition of the main lipoprotein fractions (VLDL, LDL-1, LDL-2 and HDL) was studied initially in 15 patients with Broad-beta disease. Analytical isoelectric focusing of urea-soluble apo-VLDL and apo LSL-1 demonstrated a variant pattern of the polymorphic Apoprotein E with a deficient Apo E-III band in all patients. The Apo E-III deficiency pattern was seen in only six out of 304 hyperlipidaemic controls. These six Apo E-III deficient controls had characteristic signs of Broad-beta disease, and thus represented patients not previously recognized as having the disorder. The Apo E focusing patterns were constant on repeated examinations and were stable under different metabolic conditions. The data show that Apo E-III deficiency in VLDL is a specific qualitative marker for Broad-beta disease, allowing an unequivocal diagnosis that had not been possible previously. Indirect evidence suggests that Apo E-III deficiency is the basic lipoprotein abnormality underlying the familial dyslipoproteinaemia.


Effectiveness and Safety of Tofacitinib in the Management of Ulcerative Colitis: A Brazilian Observational Multicentric Study.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease which affects the colorectal mucosa with a relapsing-remitting pattern. The therapeutic options currently available for the medical management of UC include many options. Tofacitinib is an oral small molecule, Janus kinase (JAK) inhibitor, more selective for JAK1 and JAK3, which reduces the inflammatory process involved in the pathogenesis of UC. Retrospective observational multicentric study of patients with UC who used tofacitinib in any phase of their treatment. Clinical remission and response (according to Mayo score), mucosal healing, primary and secondary loss of response, discontinuation of the drug with possible causes, and the need for dose optimization or switching to biologicals, need for surgery and adverse events were evaluated. From a total of 56 included patients, clinical remission was observed in 43.6% at week 12, 54.5% at week 26, 57.9% at week 52, and 40% at the last follow-up visit. Clinical response was observed in 71.4%, 81.8%, 89.5%, and 61.8% at the same time periods, respectively. Mucosal healing rates were 50% and 17.8% needed colectomy. Tofacitinib was effective in induction and maintenance of clinical response and remission rates, compatible to other international real-word studies and meta-analyses.


Alloimmunization in two multitransfused patient populations.
A retrospective study was undertaken to determine the frequency of alloimmunization in two multitransfused patient populations. Three hundred eighteen unselected patients whose transfusion records were available were studied. One hundred fifty-seven patients had sickle cell disease (SCD) and 161 had thalassemia. Forty-four antibodies were detected in 23 of the 99 transfused SCD patients. The predominate antibodies were in the Rh group: seventeen were anti-rh"(E), eight were anti-rh'(C), and four were anti-rh'w(Cw). Of the remaining antibodies, five were anti-Kell, three were anti-Jka, two were anti-Jkb, three were anti-Fya, one was anti-Bga, and one was anti-S. In the thalassemic patients, six antibodies were detected in 4 of the 39 transfused patients. Of these, there were two anti-Kell and one anti-Rho (D), anti-rh'(C), anti-rh'w(Cw), and anti-Fya each. Although the SCD patients were more likely to have been transfused at the parent institution than were the thalassemic patients (69% vs. 24%, p less than 0.05), the frequencies of alloimmunized patients, the total number of antibodies, and the number of Rh antibodies did not differ significantly (p greater than 0.05) for transfused patients in the two populations.


Spirocyclohexadienone-Type Neolignans with Neuroprotective and Neurite Outgrowth Enhancing Activities from Magnolia liliiflora.
Three rare spirocyclohexadienone-type neolignans, magnoflorins A-C (1-3), and three known analogs (4-6), were isolated from the leaves of Magnolia liliiflora. Magnoflorin D (4) was obtained from natural resources for the first time. The chemical structures and absolute configurations of 1-4 were elucidated through detailed analysis of HR-ESI-MS, IR, 1 H, 13 C, and 2D NMR, and ECD experiments. The absolute configuration of 5 were characterized by X-ray crystallography in present study. Moreover, compounds 4 and 5 displayed moderate neuroprotective activity against corticosterone-induced PC12 cells injury at 20 μM with cell viability of 71.5±0.99 % and 73.0±1.42 %, respectively, compared to the model group with 60.83±0.93 %. Compound 6 could enhance neurite outgrowth of nerve growth factor (NGF)-induced PC12 cells at 10 μM with the differentiation rate of 11.98 %, compared with 20.49 % of 50 ng/ml NGF.


Differential expression of KRT83 regulated by the transcript factor CAP1 in Chinese Tan sheep.
Keratin 83 (KRT83) is an important keratin protein in hair development. In this study, expression of KRT83 was compared among different tissues and between 1-month-old lambs and 48-month adult of Chinese Tan sheep, which showed different fleece phenotypes. The results showed that KRT83 was only expressed in skin, and KRT83 mRNA level in skin was significantly higher in Tan lambs than in adult sheep. To further understand the expression regulation of KRT83 by transcription factors in Tan sheep, amplified sequences coving different ranges of KRT83 promoter region were inserted into a pGL3-basic vector and then transfected into sheep primary fibroblast cells. Luciferase assay indicated that the sequence from -218bp to -10bp in the KRT83 promoter induced the highest transcription activity of the vector in the fibroblast cells. Transcription factor adenylate cyclase-associated protein 1 (CAP1) was predicted by online tools within this region. Electrophoretic mobility shift assay (EMSA) confirmed binding of the purified CAP1 protein to the target core region from -88bp to -10bp, because mutation in the target core sequence resulted in failure of CAP1 binding to the target region. Moreover, overexpression of CAP1 protein led to repression of the KRT83 promoter activity in sheep primary fibroblast cells, and expression of CAP1 was lower in lambs than in adult sheep. Therefore, we concluded that CAP1 is a key transcription factor involved in negative regulation of KRT83 expression in Tan sheep skin. Our study provides new insights into the transcriptional regulation of KRT83 and further hints of its critical role in curly hair phenotype in sheep.


Importance of cytological subclassification of thyroid nodules with Bethesda category III cytology (AUS/FLUS) into architectural atypia only and nuclear atypia: A prospective study.
The objective of this study was to compare two cytological subcategories of thyroid nodules with Bethesda category III initial cytology. This was a prospective study. All patients with thyroid nodules > 1 cm were eligible and 98 patients with category III cytology were selected. Cytology was subcategorized into architectural atypia only (AA, n = 45) and nuclear atypia (NA, n = 53). All patients underwent a second fine-needle aspiration (FNA). Only patients whose second cytology was benign and ultrasonography was non-suspicious were not referred for surgery. In these patients, the nodules were considered benign. The second FNA more frequently revealed "benign cytology" in the AA subcategory (44.4% vs. 24.5% in the NA subcategory). The second cytology suggested "follicular neoplasm" or was "suspicious for follicular neoplasm" (category IV) in 5 patients (11.1%) of subcategory AA and was "suspicious for malignancy" (category V) in 13 (24.5%) of subcategory NA. Finally, malignancy was diagnosed in 15.5% of cases of subcategory AA and in 41.5% of subcategory NA. Follicular carcinoma was more frequent in subcategory AA, while classical papillary carcinoma was more frequent in subcategory NA. Excluding cases of the noninvasive encapsulated follicular variant of papillary carcinoma, malignancy was diagnosed in 11.1% of patients of subcategory AA and in 35.8% of subcategory NA. The results showed that subclassification of the Bethesda category III improves cancer risk prediction, with potential repercussions for clinical practice. Diagn. Cytopathol. 2017;45:604-607. © 2017 Wiley Periodicals, Inc.


Revision of a pull-out suture anchor in the lateral row during the suture-bridge technique: technical note.
The repeated pulling-out of a suture anchor in the lateral row despite repeated attempts at insertion during a rotator cuff repair is not uncommon with the suture-bridge technique, especially in patients with osteoporosis. We describe a simple procedure for dealing with the pull-out of a PushLock anchor in the lateral row using a suture anchor with a suture eyelet during rotator cuff repair applying the suture-bridge technique.


Characterization of bacterial spore germination using phase-contrast and fluorescence microscopy, Raman spectroscopy and optical tweezers.
This protocol describes a method combining phase-contrast and fluorescence microscopy, Raman spectroscopy and optical tweezers to characterize the germination of single bacterial spores. The characterization consists of the following steps: (i) loading heat-activated dormant spores into a temperature-controlled microscope sample holder containing a germinant solution plus a nucleic acid stain; (ii) capturing a single spore with optical tweezers; (iii) simultaneously measuring phase-contrast images, Raman spectra and fluorescence images of the optically captured spore at 2- to 10-s intervals; and (iv) analyzing the acquired data for the loss of spore refractility, changes in spore-specific molecules (in particular, dipicolinic acid) and uptake of the nucleic acid stain. This information leads to precise correlations between various germination events, and takes 1-2 h to complete. The method can also be adapted to use multi-trap Raman spectroscopy or phase-contrast microscopy of spores adhered on a cover slip to simultaneously obtain germination parameters for multiple individual spores.


Human parechovirus type 5 neurological infection in a neonate with a favourable outcome: A case report.
The majority of parechovirus A type 5 (PeV-A5) infections have been reported in patients with gastrointestinal syndromes. In contrast, a sepsis-like illness associated with PeV-A5 infection has been reported only anecdotally. Herein, we report the first case in Italy of a PeV-A5 neurological infection presenting in a neonate with a sepsis-like syndrome. The patient, a healthy male infant born at 41 weeks of gestation, was highly distressed and inconsolable, and had been crying persistently, with poor breastfeeding, since the previous day. From day 2 to day 4, the newborn was feverish with mild irritability; breastfeeding was preserved and regularly supported. His clinical condition progressively improved, with defervescence on day 4. He was discharged after 7 days, and neurological examination results indicated only mild impairment in visual fixation and vertical eye tracking and mild axial hypotonia. The Italian PeV-A5 strain was phylogenetically related to three strains detected in Denmark in 2012, as well as to one detected in Australia and one in Greece in 2015, with an average nucleotide identity of 97.9% (range 95.9-100.0%). Enterovirus/PeV infection in the newborn should be ruled out in cases of infants with unexplained fever and/or a sepsis-like syndrome and/or meningoencephalitis. An aetiological diagnosis is essential to avoid the unnecessary administration of antibiotics and to plan long-term follow-up until schooling.