Epidermal growth factor induces CD44 gene expression through a novel regulatory element in mouse fibroblasts.
Growth factors coordinately regulate a variety of genes associated with pathological states including tumor invasion and metastasis. Overexpressed epidermal growth factor receptor (EGFR) on tumor cell surfaces is associated with enhanced cell attachment and migration into extracellular matrices, which promotes tumor aggressiveness. We have demonstrated that epidermal growth factor (EGF) up-regulates the cell surface adhesion molecule CD44 at both the mRNA and protein levels on mouse fibroblasts expressing full-length wild-type EGFR (NR6-WT) but not on EGFR-deficient cells (NR6-P). This increases cell attachment to hyaluronic acid. In this investigation, transcriptional regulation of CD44 by EGF was confirmed by defining an EGF-regulatory element. By employing human CD44 gene promoter-chloramphenicol acetyltransferase (CAT) constructs transfected into NR6-WT cells, EGF inducibility was observed within a 120-base pair (bp) DNA fragment located 450 bp upstream of the RNA initiation site. Differential EGF inducibility was found among different cell lines chosen, indicating a 3.2- and 1.8-fold enhancement in DU145 cells carrying exogenous wild-type EGFR and in MCF-7 cells, respectively, while minimal EGF induction was found in cervical cancer HeLa cells. Utilizing gel shift assays, a time-dependent increase of DNA-protein complex formation was found upon EGF stimulation in NR6-WT cells but not in NR6-P cells. Based upon these observations, a novel 22-bp EGF regulatory element (ERE) (5'--604CCCTCTCTCCAGCTCCTCTCCC-583-3') was isolated from the CD44 gene promoter. This ERE conferred DNA-protein binding ability in vitro, as well as the full functional recovery of EGF inducibility of CAT activity when linked to a homologous CD44 promoter or a SV40 promoter driving a CAT reporter gene. A two-base mutation of the ERE completely eliminated its binding activity as well as its EGF inducibility of CAT expression. Our studies indicate that EGF induces CD44 gene expression through an interaction between a specific ERE and putative novel transcriptional factor so as to regulate cell attachment to extracellular matrix.


Hair cell loss as a function of age in the normal cochlea of the guinea pig.
The surface specimen technique was used to study both spiral organs of 28 normal guinea pigs of four age groups: less than 24 hours, 6 weeks, 3 months and 1 year. Damaged hair cells were recorded for the whole of each spiral organ on cochleograms. The mean percentage number of outer hair cells damaged per age group was found to increase as a power function of age. In the animals aged less than 24 hours the mean percentage of damaged outer hair cells was 0.45%; in the 6-week animals, 1.85%; in the 3-month animals, 3.19%; and in the 1-year animals, 6.82%. At all ages outer hair cell loss was maximal in the third row, and towards the apex of the cochlea. Inner hair cell loss was very slight, with a maximum of 9 damaged inner hair cells per cochlea.


Genetic Testing and Tissue Banking for Personalized Oncology: Analytical and Institutional Factors.
Personalized oncology, or more aptly precision oncogenomics, refers to the identification and implementation of clinically actionable targets tailored to an individual patient's cancer genomic information. Banking of human tissue and other biospecimens establishes a framework to extract and collect the data essential to our understanding of disease pathogenesis and treatment. Cancer cooperative groups in the United States have led the way in establishing robust biospecimen collection mechanisms to facilitate translational research, and combined with technological advances in molecular testing, tissue banking has expanded from its traditional base in academic research and is assuming an increasingly pivotal role in directing the clinical care of cancer patients. Comprehensive screening of tumors by DNA sequencing and the ability to mine and interpret these large data sets from well-organized tissue banks have defined molecular subtypes of cancer. Such stratification by genomic criteria has revolutionized our perspectives on cancer diagnosis and treatment, offering insight into prognosis, progression, and susceptibility or resistance to known therapeutic agents. In turn, this has enabled clinicians to offer treatments tailored to patients that can greatly improve their chances of survival. Unique challenges and opportunities accompany the rapidly evolving interplay between tissue banking and genomic sequencing, and are the driving forces underlying the revolution in precision medicine. Molecular testing and precision medicine clinical trials are now becoming the major thrust behind the cooperative groups' clinical research efforts.


Relaxin-like factor (RLF): a new specific marker for Leydig cells in the ovary.
Relaxin-like factor (RLF), also known as the Leydig cell insulin-like factor (Ley-I-L), is a novel member of the insulin-IGF-relaxin family of hormones and growth factors that has recently been shown to be strongly expressed in testicular Leydig cells. Expression of the RLF peptide in the human ovary and in ovarian tumors has not been studied. In the present study, the expression of the RLF peptide in the human ovary was investigated by immunohistochemistry using a specific antibody raised against human RLF. By this method, RLF was found to be expressed in hilus (Leydig) cells and theca interna cells but absent in granulosa cells, ovarian stromal cells, and surface epithelium. RLF expression was also observed in the corpus luteum, although at a lower level than in theca cells. Thirty-seven sex cord-stromal tumors and five cases of hilar Leydig cell hyperplasia were also investigated for RLF expression. RLF was found to be strongly expressed in hilar Leydig cell hyperplasia and sex cord-stromal tumors with a component of Leydig or luteinized cells. Of the analyzed theca cell tumors, two displayed a diffuse staining pattern. As expected, RLF was not expressed in granulosa cell tumors. In conclusion, RLF appears to be a useful marker for Leydig cells in the human ovary and may be a diagnostic supplement in hyperplasias and tumors derived therefrom.


Acute coronary syndrome: new advances and nursing strategies.
Glycoprotein IIb/IIIa receptor inhibitors are the newest therapy for acute coronary syndrome (ACS). This article reviews the pathophysiology of ACS, the role of glycoprotein IIb/IIIa receptor inhibitors, and nursing care for patients undergoing this therapy and coronary interventions.


Modelling in infectious diseases: between haphazard and hazard.
Modelling of infectious diseases is difficult, if not impossible. No epidemic has ever been truly predicted, rather than being merely noticed when it was already ongoing. Modelling the future course of an epidemic is similarly tenuous, as exemplified by ominous predictions during the last influenza pandemic leading to exaggerated national responses. The continuous evolution of microorganisms, the introduction of new pathogens into the human population and the interactions of a specific pathogen with the environment, vectors, intermediate hosts, reservoir animals and other microorganisms are far too complex to be predictable. Our environment is changing at an unprecedented rate, and human-related factors, which are essential components of any epidemic prediction model, are difficult to foresee in our increasingly dynamic societies. Any epidemiological model is, by definition, an abstraction of the real world, and fundamental assumptions and simplifications are therefore required. Indicator-based surveillance methods and, more recently, Internet biosurveillance systems can detect and monitor outbreaks of infections more rapidly and accurately than ever before. As the interactions between microorganisms, humans and the environment are too numerous and unexpected to be accurately represented in a mathematical model, we argue that prediction and model-based management of epidemics in their early phase are quite unlikely to become the norm.


Deterministic-Stochastic modeling: A new direction in modeling real world problems with crossover effect.
Many real world problems depict processes following crossover behaviours. Modelling processes following crossover behaviors have been a great challenge to mankind. Indeed real world problems following crossover from Markovian to randomness processes have been observed in many scenarios, for example in epidemiology with spread of infectious diseases and even some chaos. Deterministic and stochastic methods have been developed independently to develop the future state of the system and randomness respectively. Very recently, Atangana and Seda introduced a new concept called piecewise differentiation and integration, this approach helps to capture processes with crossover effects. In this paper, an example of piecewise modelling is presented with illustration to chaos problems. Some important analysis including a piecewise existence and uniqueness and piecewise numerical scheme are presented. Numerical simulations are performed for different cases.


[Rheumatoid arthritis and cardiovascular complications].
Rheumatoid arthritis is associated with increased morbidity and mortality due to cardiovascular events. Elevated concentrations of acute-phase proteins and cytokines and endothelial dysfunction, demonstrated also by lack of traditional risk factors, play an important role in these complications. Antirheumatic drug treatment can modify the frequency and severity of cardiovascular events.


Reticulocyte and erythrocyte hypochromia markers in detection of iron deficiency in adolescent female athletes.
The aim of this study was to analyse the effectiveness of new haematology parameters related to reticulocytes and mature red blood cells to differentiate pre latent and latent iron deficiency. The study included 219 female athletes (aged 15-20 years) representing volleyball, handball, cycling, canoeing, cross-country skiing, swimming and judo. To assess iron status the concentration of ferritin, soluble transferrin receptor (sTfR), iron and total iron binding capacity (TIBC) were determined in serum. In addition to blood morphology, the mean cellular haemoglobin content in erythrocytes (CH) and reticulocytes (CHr), mean cellular haemoglobin concentration in reticulocytes (CHCMr), the percentage of erythrocytes (HYPOm) and reticulocytes (HYPOr) with decreased cellular haemoglobin concentration, the percentage of erythrocytes (LowCHm) and reticulocytes (LowCHr) with decreased cellular haemoglobin content, and percentage of erythrocytes with decreased volume (MICROm) were determined. Subjects with ferritin <30 ng/ml were classified as having stage I (pre-latent) iron deficiency (ID). The second stage (latent ID) was diagnosed when low ferritin was accompanied by elevated sTfR and/or elevated TIBC values. The frequency of ID (without anaemia symptoms) was high, amounting to 60% (stage I in 45%, stage II in 15% of subjects). In subjects with stage I ID significant changes in haematological variables concerned mainly reticulocytes: CHCMr (p<.001), CHr (p<.05), LowCHr (p<.05), HYPOr (p<.001) in comparison to normal iron stores. In athletes with latent ID, there were also significant changes (p<.001) in many indices of mature red blood cells, i.e. haemoglobin concentration (Hb), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), CH, %LowCHm, as well as %MICROm (p<.01) in relation to the group without iron deficiency. The main finding of this study was that the diminished or exhausted iron stores had already caused changes in reticulocytes, and intensified iron deficiency (stage II) increased changes in both reticulocytes' and erythrocytes' hypochromia indices, while microcythaemia symptoms appeared later. This suggests that the markers of hypochromia relating especially to reticulocytes are useful for diagnosis of early ID in athletes with absence of an acute phase reaction.


[Primary prevention of chronic non-communicable diseases and acetylsalicylic acid: ambiguity of opinions].
Chronic noninfectious diseases (cardiovascular, bronchopulmonary, oncological diseases and diabetes mellitus) are presently the most common cause of death worldwide, with cardiovascular diseases (CVD) being predominant. For this reason, the key goal of a physician is not only to treat but also to prevent diseases. Acetylsalicylic acid (ASA) is considered one of the most effective drugs for secondary prevention of CVD. However, the use of ASA for primary prevention is still debated. Results of many studies of ASA are inconsistent. Some studies have suggested that using ASA in patients aged 40-70 with a high 10-year risk of CVD and a low risk of bleeding may reduce the incidence of CVD. Administration of ASA to patients with a high or medium risk of CVD is also considered.


Anticancer medicines (Doxorubicin and methotrexate) conjugated with magnetic nanoparticles for targeting drug delivery through iron.
The uptake of iron is increased by cancer cells. Iron magnetic nanoparticles (MNP) can be used as a nanovehicle for immobilization of anticancer medicines and to integrate them at a target site. The anticancer medicines doxorubicin (DOX) and methotrexate (MTX) were immobilized separately and in combination onto MNP by a glutaraldehyde activation method and confirmed by magnetic nanoparticles linked immunosorbent assay (MagLISA) and Fourier-transform infrared (FTIR) spectroscopy. The phenol peaks of DOX and MTX at 2896.6 cm⁻¹ to 2912.5 cm⁻¹ in FTIR spectra of immobilized medicines indicated the conjugation. Affinity-purified anti-DOX and anti-MTX antibodies were used to evaluate the coupling of DOX and MTX onto MNP, and the binding was found 34.6% to 37.2% and 51.8% to 54.3% separately, respectively. The immobilization of DOX and MTX in combination onto MNP was 18% and 27%, respectively. HeLa and B cells were cultured with DOX-MNP, MTX-MNP, and DOX-MNP-MTX separately, and MagLISA indicated that the binding of DOX-MNP/MTX-MNP was 41.5% to 45% with HeLa cells and 20% to 26% with B cells. No significant difference was observed in binding of DOX-MNP-MTX with HeLa and B cells. Results also indicated that the release of medicines at pH 5.0 is more (39% to 44%) than at pH 7.4 (3.7% to 10.2%). Sixteen to 22% more killing effect was observed on HeLa cells than on B cells. In immunohistochemical staining, more deposition of brown color on HeLa cells than on B cells may be due to more expression of iron-binding sites on cancer cells. The dual property of MNP can be used for binding of medicines and for targeting drug delivery.


Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450.
The liver is a sexually dimorphic organ in many species, including humans. In rodent models, dramatic sex differences characterize the expression of numerous plasma proteins, receptors and other signaling molecules, and enzymes of steroid and foreign compound metabolism, including members of the cytochrome P450 (CYP) superfamily. The sexual dimorphism of liver gene expression is dictated by the temporal pattern of plasma growth hormone (GH) stimulation, which is intermittent and highly pulsatile in males and more frequent in females. Many liver-specific genes, including CYP genes, are regulated by the coordinated action of multiple hepatic nuclear factors (HNFs) through a complex transcriptional hierarchy. These HNFs are proposed to collaborate with the GH pulse-activated latent cytoplasmic transcription factor STAT5b to regulate the sex-dependent expression of liver CYPs. This hypothesis is supported by the finding that certain HNFs are regulated by GH and exhibit a differential responsiveness to the sex-specific pattern of GH secretion. In particular, recent studies of an HNF4alpha-deficient mouse model demonstrate an essential role for this nuclear receptor in regulating several liver-enriched transcription factors and sexually dimorphic CYPs in liver in vivo. Further studies on the mechanisms by which HNF4alpha and other liver factors respond to GH may expand our understanding of the mechanisms by which GH, via the coordinated action of HNFs and STAT5b, regulate sexually dimorphic liver gene expression.


Oxidative stability of canola oil by Biarum bovei bioactive components during storage at ambient temperature.
In this study, antioxidative activities of aqueous extract of Biarum bovei (BBE) in stabilizing of canola oil during storage at 20°C was evaluated. For this purpose, the total phenolic (TP), flavonoids (TFC), and tocopherol content (TTC) of the extract were determined and β-carotene bleaching system was used to assess the antioxidant efficacy of BBE. The amount of TP, TFC, and TTC in BBE indicated high antioxidant activity. So, different concentrations (0, 200, 800, and 1400 ppm) of BBE and butylatedhydroxyanisole (BHA; 100 ppm), were added to canola oil for 60 days at 20°C. Peroxide value (PV), carbonyl value (CV), Total polar compounds (TPC), acid value (AV), iodine values (IV), and conjugated dienes (CD) were employed to evaluate the BBE effect on canola oil stabilizing. Results indicated that 1,400 ppm of BBE exhibited stronger antioxidant activity in canola oil than BHA.


Correlation of duplex scanning and two plane angiography in patients with symptomatic carotid stenosis.
The correlation between flow velocity and percent stenosis in carotid arteries was assessed in 43 symptomatic patients (86 carotids) using duplex scanning and angiography. Duplex scanning evaluation was performed using the ATL Ultramark 4 duplex scanner with the 5-7.5-10 MHz probe. Using the ratio of peak velocity in the internal carotid in systole (VICA) to the end diastolic velocity in the common carotid (VCCA) we studied its correlation with the percent stenosis observed by angiography. A good correlation (r = .95) was found. The graph obtained indicates that a significant (greater than 50%) stenosis may be graded by the VICA/VCCA ratio with a high degree of accuracy (97%). This may be useful not only for screening patients to select for angiography and surgery but also to follow up the natural history of carotid stenosis.


Tyrosine-phosphorylation of the scaffold protein ADAP and its role in T cell signaling.
The Adhesion and Degranulation promoting Adaptor Protein (ADAP) is phosphorylated upon T cell activation and acts as a scaffold for the formation of a signaling complex that integrates molecular interactions between T cell or chemokine receptors, the actin cytoskeleton, and integrin-mediated cellular adhesion and migration. This article reviews current knowledge of the functions of the adapter protein ADAP in T cell signaling with a focus on the role of individual phosphotyrosine (pY) motifs for SH2 domain mediated interactions. The data presented was obtained from literature searches (PubMed) as well as the authors own research on the topic. Expert commentary: ADAP can be regarded as a paradigmatic example of how tyrosine phosphorylation sites serve as dynamic interaction hubs. Molecular crowding at unstructured and redundant sites (pY595, pY651) is contrasted by more specific interactions enabled by the three-dimensional environment of a particular phosphotyrosine motif (pY571).


Usefulness of cell counter-based parameters and formulas in detection of beta-thalassemia trait in areas of high prevalence.
The present study aimed to retrospectively evaluate the usefulness of cell counter-based parameters and formulas in beta-thalassemia trait (BTT) detection. The study included 170 BTT cases (hemoglobin [Hb]A(2) >4.0% [0.04]) and 30 non-BTT cases (HbA(2), 2.3%-3.5% [0.02-0.04]). Depending on the hemoglobin level and iron deficiency, the BTT group was further classified into classic BTT (n = 112) and BTT with iron deficiency anemia (n = 58). The RBC count, MCH, MCV, RDW, and Shine and Lal, Mentzler, Srivastava, England and Fraser, Ricerca, and Green indexes were applied. For the first time in the population of India, these 10 cell counter parameters and manual formulas were compared with high-performance liquid chromatography-derived HbA2 levels for deriving a cost-effective alternative method; and receiver operating characteristic curves were applied. We found that the Shine and Lal, Srivastava, and Mentzler indexes, MCV, and MCH have better discriminative function than the RBC count and red cell distribution width and their related formulas.


Dimensions of reading: a study of the beliefs of language and literature preservice teachers.
This study aims to analyze the beliefs that future Language and Literature teachers hold regarding reading. This work is part of a broader research endeavor focused on the reading habits and practices of teachers in training and their role as prospective mediators since the way in which they perceive reading significantly impacts the mediation processes they undertake in their teaching practices to cultivate readers. To achieve these objectives, a multiple case study is conducted, involving interviews with 1st-year students (n = 15), 3rd-year students (n = 15), and 5th-year students (n = 15) enrolled in Language Pedagogy programs across three universities affiliated with the Chilean Council of Rectors. For data analysis, a content analysis approach is employed, supported by NVivo 12. The findings reveal that beliefs about reading primarily fall into two dimensions: academic and personal, with the former exhibiting clearer definition and characterization. This can be attributed to the influence of the disciplines integrated into their education, namely literature and linguistics. In conclusion, it is imperative to address the social dimension of reading during the initial teacher education program, as this aspect is not emphasized by preservice teachers, despite its pivotal role in shaping their identity as reading mediators within the context of their teaching practice.


A reappraisal of the reported dose equivalents at the boundary of the University of California Radiation Laboratory during the early days of Bevatron operation.
The Bevatron of the Lawrence Berkeley National Laboratory operated with no permanent shielding-roof from 1954 to 1962. Neutron fluences measured at the laboratory perimeter reached a maximum in 1959, and were reported as an annual dose equivalent of 8.1 mSv (54% of the then operative radiation limit). The addition of temporary local shielding and improved operational techniques subsequently led to a steady decline in dose equivalent at the laboratory perimeter. A permanent concrete shielding-roof was constructed in 1962. In those early years of operation the reported dose equivalent, H, was derived from a measured total neutron fluence, phi, and an estimated spectrum-weighted fluence to dose equivalent conversion coefficient, (g), where H= (g) phi. The uncertainty in H was almost entirely due to the uncertainty in (g). While the measurements of phi were accurate the estimates of (g) were quite crude and depended upon measurements of average neutron energy, on assumptions about the shape of the neutron energy spectrum, and primitive values of fluence to dose equivalent conversion coefficients for monoenergetic neutrons. These early reported dose equivalents were known to be overestimated. This paper has reappraised the dose equivalents in the light of better information now available. Environmental neutron spectra have been calculated which more accurately correspond to the operational conditions of the Bevatron in the 1950s and early 1960s. than did those spectra available at that time. A new fluence to dose equivalent conversion function based on the latest data and for isotropic irradiation geometry was developed. From these two parameters better estimates of the coefficient (g) were determined and compared with the earlier values. From this reappraisal it is shown that the early reported dose equivalents were conservative by a factor of at least five.


Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21.
Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21(-/-) HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. The combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment.


An All-Organic Aqueous Battery Powered by Adsorbed Quinone.
The need for cost-effective, safe energy storage has led to unprecedentedly complex designs of materials and structures to meet stringent requirements. Yet, it remains a question whether we can eventually afford the manufacturing of these new materials and structures at a practical cost. Here, we introduce a new approach toward an all-organic aqueous battery through one-step, solution-phase adsorption. In this battery, two quinone molecules with different redox potentials adsorb onto two porous carbon electrodes to serve as the negative and the positive electrodes. For the negative side, cyclic voltammetry shows a high surface coverage of 66 pmol/cm2 for the adsorbed quinone (anthraquinone-2,7-disulfonate), which enables a stable capacity of 77 mAh/g. The full battery, operating in 1 M sulfuric acid, delivers more than 80% of its capacity at rates of up to 60C, and it retains more than 70% of the capacity after 600 cycles. As the battery adopts the typical build of a supercapacitor, this adsorption-based approach should apply broadly to achieve low-cost, safe storage. The work also provides a quantitative account of the electrochemistry of quinone adsorbed on carbon, which bears significance in the exploitation of quinone molecules in various electrochemical applications.


Defect of an early event of glucose metabolism in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a non-insulin-dependent diabetes mellitus (NIDDM) model.
Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed that the distribution of plasma membrane content of insulin-regulated glucose transporter in skeletal muscle was reminiscent of that in human non-insulin-dependent diabetes mellitus (NIDDM). To obtain more information on the cellular mechanisms of muscle insulin resistance, hexokinase activities were measured in the skeletal muscle of OLETF rats. The results showed that the activity of the type II enzyme in the diabetic rats was significantly decreased (P < 0.05) compared with Long-Evans Tokushima Otsuka (LETO) control rats. No significant differences in the activity of the type I hexokinase were observed between these rats. Western blot analysis showed that the protein content of the type II in OLETF rats was also significantly lower than that in LETO rats (P < 0.05). After insulin stimulation, the intramuscular content of glucose 6-phosphate, which regulates glycogen synthesis in skeletal muscle, was significantly decreased in OLETF rats (P < 0.01). However, glycogen synthase activity in vitro and intramuscular lactate concentration in these rats did not show significant differences. These results suggest that the G6P content of the diabetic rats is decreased as a result of an impaired early event of glucose metabolism, indicating that the molecular defects of skeletal muscle in OLETF rats are similar to those in NIDDM patients.


Multipopulation survey designs: five types with seven shared aspects.
"Five types of multipopulation surveys are defined and described: periodic surveys; multidomain designs; multinational survey designs; cumulated and combined samples; and controlled observations or quasi- experimental designs. I emphasize the deliberate designs of these surveys, not the mere post hoc or ad hoc utilization of survey results. Most importantly, I emphasize a sharp distinction between seven listed aspects. Similarity and standardization of the survey aspects (definitions, methods, measurements) are essential to avoid biases in comparisons, though admittedly difficult. In contrast, flexibility in sampling designs and sizes, to reduce variances, is permissible, also desirable to reduce variances and costs." (SUMMARY IN FRE)


A comment on the position dependent diffusion coefficient representation of structural heterogeneity.
Experimental studies of the variation of the mean square displacement (MSD) of a particle in a confined colloid suspension that exhibits density variations on the scale length of the particle diameter are not in agreement with the prediction that the spatial variation in MSD should mimic the spatial variation in density. The predicted behavior is derived from the expectation that the MSD of a particle depends on the system density and the assumption that the force acting on a particle is a point function of position. The experimental data are obtained from studies of the MSDs of particles in narrow ribbon channels and between narrowly spaced parallel plates and from new data, reported herein, of the radial and azimuthal MSDs of a colloid particle in a dense colloid suspension confined to a small circular cavity. In each of these geometries, a dense colloid suspension exhibits pronounced density oscillations with spacing of a particle diameter. We remove the discrepancy between prediction and experiment using the Fisher-Methfessel interpretation of how local equilibrium in an inhomogeneous system is maintained to argue that the force acting on a particle is delocalized over a volume with radius equal to a particle diameter. Our interpretation has relevance to the relationship between the scale of inhomogeneity and the utility of translation of the particle MSD into a position dependent diffusion coefficient and to the use of a spatially dependent diffusion coefficient to describe mass transport in a heterogeneous system.


On the Link Between Emotionally Driven Impulsivity and Aggression: Evidence From a Validation Study on the Dutch UPPS-P.
The UPPS-P seems to be a promising instrument for measuring different domains of impulsivity in forensic psychiatric patients. Validation studies of the instrument however, have been conducted only in student groups. In this validation study, three groups completed the Dutch UPPS-P: healthy student ( N = 94) and community ( N = 134) samples and a forensic psychiatric sample ( N = 73). The five-factor structure reported previously could only be substantiated in a confirmatory factor analysis over the combined groups but not in the subsamples. Subgroup sample sizes might be too small to allow such complex analyses. Internal consistency, as assessed by Cronbach's alpha, was high on most subscale and sample combinations. In explaining aggression, especially the initial subscale negative urgency (NU) was related to elevated scores on self-reported aggression in the healthy samples (student and community). The current study is the second study that found a relationship between self-reported NU and aggression highlighting the importance of addressing this behavioural domain in aggression management therapy.


Prediction of human drug metabolizing enzyme induction.
New chemical entities are routinely screened in vitro and in vivo for their ability to induce cytochrome P450s (CYP), other drug-metabolizing enzymes and possibly transporters in an attempt to more accurately predict clinical parameters such as drug-drug interactions and clearance in humans. Some of these potential therapeutic agents can cause induction of the metabolism of another molecule or auto-induction thereby increasing their own metabolism and elimination, as well as potentially any molecules metabolized by the same enzyme(s). Key CYPs in the 1A, 2B, 2C, and 3A families have all been shown to be inducible. It would be clearly advantageous to know the potential for a compound to induce drug metabolizing enzymes or transporters prior to clinical development, and many in vitro systems have been developed for this purpose. Newer computational technologies are also being applied in order to attempt to predict induction from the molecular structure alone before a molecule is even synthesized or tested. This review will cover the various in vitro and in silico methods developed for prediction of key inducers of CYPs and other proteins, as well as the limitations of such technologies and applications in the future.


Organization of the DMSO respiratory operon of Rhodobacter capsulatus and its consequences for homologous expression of DMSOR/TMAOR.
In this report we describe the organization of the respiratory operon from the non-sulfur photosynthetic bacterium Rhodobacter capsulatus and its consequences for homologous expression of recombinant dimethylsulfoxide/trimethylamine N-oxide reductase (DMSOR/TMAOR). This enzyme is of special interest since molybdopterin dinucleotide is its only cofactor. Overexpression of the dmsA gene and production of active enzyme is not possible in E. coli because this bacterium is unable to supply the required complex molybdopterin cofactor. To investigate the catalytic mechanism and binding of the cofactor by structure-based site-directed mutagenesis, and to ensure sufficient production and incorporation of the complex cofactor, we designed a system for homologous expression in R. capsulatus.


Ultrasound evaluation of uterine healing after laparoscopic intracapsular myomectomy: an observational study.
Can uterine scar healing after laparoscopic intracapsular myomectomy (LIM) be adequately monitored by traditional two-dimensional (2D) ultrasound (US) and Doppler velocimetry? The myometrial area of the scar after LIM can be followed by 2D US and Doppler velocimetry. Apart from post-surgical adhesions, the main concern linked to laparoscopic myomectomy is the quality of healing of the myometrial incision: it has been suggested that US could be useful for assessing uterine scars after myomectomy. However, no diagnostic method has yet been widely accepted to assess the healing process. A cohort prospective study (level of evidence II-2), run in University-affiliated hospitals: 149 women with symptomatic uterine fibroids (UFs) underwent LIM, between January 2007 and October 2011. During follow up 13 patients withdrew from the study. After LIM, all patients were followed by traditional 2D US scanning and Doppler velocimetry on Days: 0, 1, 7, 30 and 45. Authors evaluated: number, size and location of UFs, scar diameter and Doppler velocimetry and resistance index (RI) of the uterine arteries, at their ascending branch. The uterine examination showed a significant (P < 0.05) progressive reduction of uterine scar area from 78% of the previous UF location on the first day, to 19% on 30th day, and <4% on the 45th day. There was no correlation with the size of the fibroid or the relative reduction in the size of the scar, on both Days 1 and 45. There was a significant (P < 0.05) increase in the RI of the ipsilateral uterine arteries from 0.65 on the first post-operative day to 0.83 after 7 days followed by a decrease to 0.71 on the 30th and 0.61 on the 45th post-operative day. This is a cohort investigation on a limited number of patients and it does not surgically compare LIM and 'classic' myomectomy in the scar US follow up. LIM avoided intraoperative bleeding and excessive tissue damage, as post-operative US follow up showed, with just two intra-myometrial hematomas (1.5%). The 2D US and Doppler velocimetry, a non-invasive safe method to check the myometrium after LIM, can detect post-operative hematoma and disechogenic, heterogeneous or ill-defined scar area, all unfavorable signs for myometrial scarring. Moreover, Doppler transvaginal monitoring, evaluating the pulsatility index (PI) and RI of the uterine arteries at their ascending branch, could identify patients with altered PI and RI parameters, possible markers of impaired wound healing.


Complexity of macrophage migration inhibitory factor (MIF) and other angiogenic biomarkers profiling in pulmonary arterial hypertension.
Macrophage migration inhibitory factor (MIF) and 22 a priori selected biomarkers were measured from pulmonary arterial hypertension (PAH) patients. Significant positive correlations were found between MIF and several angiogenic factors suggesting a possible MIF regulation role in PAH angiogenesis and pathobiology, but simultaneously highlighting the biomarkers profiling complexity in PAH.


In vitro effects of recombinant interleukin 7 on growth and differentiation of bone marrow pro-B- and pro-T-lymphocyte clones and fetal thymocyte clones.
We have studied the effects of recombinant (r) interleukin 7 (IL-7) on growth and differentiation of marrow pro-B-lymphocyte clones (CB/Bm7, LyD9, LyB9), marrow pro-T-lymphocyte clones (C4-77/3, C4-86/18, C4-95/16), and fetal thymocyte clones (FTH5, FTA2, FTD5) in the presence or absence of the bone marrow stroma clone RP.0.10, which was selected for its ability to promote differentiation of the pro-B clones. rIL-7 alone stimulated some DNA synthesis (measured by [3H]thymidine uptake) but not actual growth (increase in cell number) of the pro-B clones. Antibodies against IL-4 and IL-6 or against receptors for IL-2, IL-3, and IL-5 did not inhibit this effect of rIL-7 on the pro-B clones. rIL-7 alone or in various combinations with other cytokines (from rIL-1 alpha to rIL-6) could not induce differentiation of the pro-B clones into IgM+ B cells regardless of the presence of lipopolysaccharide (LPS). The RP.0.10 marrow stroma cells by themselves do not support the growth of the pro-B clones. However, the pro-B clones grew when cultured with rIL-7 and monolayers of the RP.0.10 stroma cells. While the RP.0.10 stroma cells induced the pro-B clones to differentiate into IgM+ B cells but not T3+ T cells when cultured in the presence of LPS and rIL-3, the B-cell progenitor clones gave rise to significantly higher numbers of IgM+ B cells (up to 63%) and to many more B cells expressing higher levels of surface IgM when cocultured with rIL-7, LPS, and RP.0.10 stroma cells. The pro-B clones also generated IgM+ B cells (up to 20%) when cocultured with RP.0.10 stroma cells and rIL-7 in the absence of LPS. By using culture plates designed for testing requirements for cell-cell contact, we found that cell interactions between the pro-B cell and the marrow stroma cell are essential to induce rearrangement and expression of the immunoglobulin genes in the pro-B clones. Possible mechanisms to account for the remarkable effects of rIL-7 in the presence of RP.0.10 stroma cells on both growth and differentiation of the pro-B clones are discussed. Finally, rIL-7 alone or together with RP.0.10 stroma cells neither supported proliferation nor induced differentiation into T3+ T cells or IgM+ B cells of the marrow pro-T clones or the fetal thymocyte clones. In light of these findings, we postulate that the interaction of the pluripotential stem cell with marrow stroma cells like RP.0.10 and the availability of IL-7 could play a critical role in the commitment to develop along the B-lymphocyte pathway.


Ship Target Automatic Detection Based on Hypercomplex Flourier Transform Saliency Model in High Spatial Resolution Remote-Sensing Images.
Efficient ship detection is essential to the strategies of commerce and military. However, traditional ship detection methods have low detection efficiency and poor reliability due to uncertain conditions of the sea surface, such as the atmosphere, illumination, clouds and islands. Hence, in this study, a novel ship target automatic detection system based on a modified hypercomplex Flourier transform (MHFT) saliency model is proposed for spatial resolution of remote-sensing images. The method first utilizes visual saliency theory to effectively suppress sea surface interference. Then we use OTSU methods to extract regions of interest. After obtaining the candidate ship target regions, we get the candidate target using a method of ship target recognition based on ResNet framework. This method has better accuracy and better performance for the recognition of ship targets than other methods. The experimental results show that the proposed method not only accurately and effectively recognizes ship targets, but also is suitable for spatial resolution of remote-sensing images with complex backgrounds.


[Antagonistic activity of the rumen bacteria, Enterococcus faecium and Staphylococcus warneri].
The bacterial strains E. faecium and S. warneri were tested for their antagonistic activities, and/or for the antimicrobial spectrum of bacteriocin-like substances produced by these bacteria. Isolates of rumen and non-rumen origin were used as indicator strains (Tab. I). All the isolates (except the strains SW48 and EF24c as indicators of rumen origin) produced bacteriocin-like substances inhibiting the growth of at least one of the series of the nine indicators used while clear inhibition zones 2-10 mm prevailed (Tabs. II, III). Among the enterococci, the inhibition of non-rumen indicators was more intensive in comparison with the indicators of rumen origin, but the inhibition zones were only 2-5 mm. In general, the staphylococci showed the antagonistic activity with the lower antimicrobial spectrum in comparison with the enterococci. None of the tested strains inhibited the growth of the indicator E. faecium A26. The summary results show that the growth of both gram-positive and gram-negative bacteria was inhibited. The prolonged cultivation time did not influence the antagonistic activity of the tested strains. In the strains EF35, SW34 and SW98, the antagonistic activity was maintained after trypsin treatment. But in the other strains, this treatment led to the loss of the antagonistic activity. The use of pronase P resulted in the loss of the activity in the strains SW24, EF35 and EF26/142. The use of pronase P did not lead to the loss of the activity in the other tested isolates (Tab. IV).(ABSTRACT TRUNCATED AT 250 WORDS)


Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment.
Obstetric cholestasis (OC) may cause severe pruritus in the mother and lead to fetal distress and stillbirth. The etiology of OC is multifactorial, but includes inherited dysfunction of bile canalicular transporters. One of these, multidrug resistant protein 3 (MDR3), a phospholipid transporter, when dysfunctional is associated with elevated levels of gamma glutamyl transpeptidase (GGT). The aim of the present study was to assess the incidence of OC associated with elevated GGT. We compared the natural history of a cholestatic pregnancy and the efficacy of ursodeoxycholic acid (URSO) in OC patients grouped according to a normal or raised GGT level. Eighty-one patients with OC were analyzed. OC was diagnosed in patients with pruritus and elevated serum bile acids (SBA). Fifty-seven consenting volunteer patients (70%) were treated with URSO. Elevated GGT at presentation was found in 21 patients (30%) and was associated with significantly higher serum levels of aspartate transaminase (AST), bilirubin (BIL) and SBA. OC presented at approximately the same gestation week in both groups of patients. In patients not treated with URSO, liver function tests (LFT) showed no significant change from the time of diagnosis to delivery. Patients from both groups responded to URSO with significant improvement in their AST and alanine aminotransferase (ALT) levels, but SBA fell significantly only in the normal GGT group. An elevated GGT occurs in less than one-third of patients with OC in the UK and, when present, is associated with greater impairment of LFT, but no difference in gestational age at onset. Treatment with URSO appears to be safe and significantly improves LFT in patients with OC, with the exception of SBA in the high GGT group.


INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis.
To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH). The effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/ob (ob/ob) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/ob (ob/ob) NASH mice were first dosed with INT-767 (3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767 (3 and 10 mg/kg) to obeticholic acid (OCA) (10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57Bl/6 mice on standard chow. C57Bl/6 mice were orally dosed with INT-767 or OCA (1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry. INT-767 dose-dependently (3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation (assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study (16 wk), the FXR agonists OCA (10 and 30 mg/kg) and INT-767 (3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.


Interpretation of interleukin-2 receptor alpha positive cells during induction chemotherapy for adult acute myelogenous leukaemia patients.
To correlate clinical outcomes with the expression of interleukin-2 receptor alpha (CD25) positive cells during induction chemotherapy (IC) in adult patients with acute myeloid leukaemia (AML), we investigated the prognostic importance of subsets of peripheral blood (PB) CD45+CD25+ cells. Seventy-five patients with newly diagnosed AML received the same initial IC; and serial PB samples were taken. The gated CD45/CD25 cell populations were used to compare the intensity of immunophenotypic signals based on the treatment timeline. Patients who responded poorly to IC demonstrated exceptionally higher levels of PB CD45+CD25+ cells by percentage (p = 0.003) or by absolute count (p = 0.046) on the seventh day (D + 7) of initial IC. In addition, patients in complete remission (CR) (n = 61) demonstrated relatively lower levels of steady PB CD45+CD25+ after standard IC. These results suggest that the expression of CD25 can be used to predict the response to IC during an early period of treatment.


Study of the mouse sortilin gene: Effects of its transient silencing by RNA interference in TM4 Sertoli cells.
Using databases of the mouse genome in combination with a sequence deduced from a mouse sortilin cDNA originated in our laboratory, we found the sortilin gene to map to a region of chromosome 3. The mouse sortilin gene contains 19 short exons separated by introns of various sizes. The study elucidated the exon-intron boundaries. Some introns extend over more than 24 kb. In the cytoplasmic domain of the translation product, we found a dileucine motif and three other motifs known to constitute the active sorting signal of the mannose 6-phosphate receptor (M6P-R). We also tested the hypothesis that sortilin is involved in the sorting of prosaposin (SGP-1) to the lysosomes. Prosaposin was initially identified in Sertoli cells, found in large amounts in the lysosomal compartment and implicated in the degradation of residual bodies released by the spermatids during spermiation. Interestingly, the targeting of prosaposin to the lysosomes is independent of the M6P-R. This investigation demonstrated that sortilin was required for the trafficking of prosaposin to the lysosomes in TM4 cells. The requirement of sortilin was shown using a siRNA probe to block the translation of sortilin mRNA. Sortilin-deficient cells were not able to route prosaposin to the lysosomal compartment but continue to transport cathepsin B, since this hydrolase uses the M6P-R to be routed to the lysosomes. These results indicate that sortilin appears to be involved in the lysosomal trafficking of prosaposin.


The prominent T wave: electrocardiographic differential diagnosis.
The prominent T wave is an abnormal T-wave morphology encountered in the earliest phase of ST-segment elevation acute myocardial infarction (AMI). Prominent T waves, however, are associated with other diagnoses, including hyperkalemia, early repolarization, and left ventricular hypertrophy (LVH). This article focuses on the electrocardiographic differential diagnosis of the prominent T wave with the presentation of 4 illustrative cases. We also recommend that the designation hyperacute should refer exclusively to the prominent T waves of ST-segment elevation AMI.


Guidewire-assisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.
Cannulation techniques have been recognized as being important in causing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, considerable controversy exists about the usefulness of the guidewire-assisted cannulation technique for the prevention of PEP. To assess the effectiveness and safety of the guidewire-assisted cannulation technique compared to the conventional contrast-assisted cannulation technique for the prevention of PEP in people undergoing diagnostic or therapeutic ERCP for biliary or pancreatic diseases. For the previous version of this review, we searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL and major conference proceedings, up to February 2012, with no language restrictions. An updated search was performed on 26 February 2021 for the current version of this review. Two clinical trial registries, clinicaltrials.gov and WHO ICTRP, were also searched in this update. Randomized controlled trials (RCTs) comparing the guidewire-assisted cannulation technique versus the contrast-assisted cannulation technique in people undergoing ERCP. Two review authors conducted study selection, data extraction, and methodological quality assessment independently. Using intention-to-treat analysis with random-effects models, we combined dichotomous data to obtain risk ratios (RR) with 95% confidence intervals (CI). We assessed heterogeneity using the Chi² test (P < 0.10) and I² statistic (> 50%). To explore sources of heterogeneity, we conducted a priori subgroup analyses according to trial design, publication type, risk of bias, use of precut sphincterotomy, inadvertent guidewire insertion or contrast injection of the pancreatic duct (PD), use of a PD stent, cannulation device, and trainee involvement in cannulation. To assess the robustness of our results, we carried out sensitivity analyses using different summary statistics (RR versus odds ratio (OR)) and meta-analytic models (fixed-effect versus random-effects) and per-protocol analysis. 15 RCTs comprising 4426 participants were included. There was moderate heterogeneity among trials for the outcome of PEP (P = 0.08, I² = 36%). Meta-analyses suggest that the guidewire-assisted cannulation technique probably reduces the risk of PEP compared to the contrast-assisted cannulation technique (RR 0.51, 95% CI 0.36 to 0.72, 15 studies, moderate-certainty evidence). In addition, the guidewire-assisted cannulation technique may result in an increase in primary cannulation success (RR 1.06, 95% CI 1.01 to 1.12, 13 studies, low-certainty evidence), and probably reduces the need for precut sphincterotomy (RR 0.79, 95% CI 0.64 to 0.96, 10 studies, moderate-certainty evidence). Compared to the contrast-assisted cannulation technique, the guidewire-assisted cannulation technique may result in little to no difference in the risk of post-sphincterotomy bleeding (RR 0.87, 95% CI 0.49 to 1.54, 7 studies, low-certainty evidence) and perforation (RR 0.93, 95% CI 0.11 to 8.23, 8 studies, very low-certainty evidence). Procedure-related mortality was reported by eight studies, and there were no cases of deaths in both arms (moderate-certainty evidence). Subgroup analyses suggest that the heterogeneity for the outcome of PEP could be explained by differences in trial design. The results were robust in sensitivity analyses. There is moderate-certainty evidence that the guidewire-assisted cannulation technique probably reduces the risk of PEP compared to the contrast-assisted cannulation technique. There is low-certainty evidence that the guidewire-assisted cannulation technique may result in an increase in primary cannulation success. There is low- and very low-certainty evidence that the guidewire-assisted cannulation technique may result in little to no difference in the risk of bleeding and perforation. No procedure-related deaths were reported. Therefore, the guidewire-assisted cannulation technique appears to be superior to the contrast-assisted cannulation technique considering the certainty of evidence and the balance of benefits and harms. However, the routine use of guidewires in biliary cannulation will be dependent on local expertise, availability, and cost. Future research should assess the effectiveness and safety of the guidewire-assisted cannulation technique in the context of other pharmacologic or non-pharmacologic interventions for the prevention of PEP.


[A possible analgesic effect of nicotine on postoperative pain].
Since postoperative pain often is undermanaged, and opioids, although being efficient analgesics, have undesirable side effects, attention has turned towards adjuvant therapies, among them nicotine. We present seven studies of which six show an effect of nicotine on postoperative pain when given in a low dose, with short time of exposure and to non-smokers. Other possible confounders are gender and type of anaesthesia. Nicotine seems to increase the occurrence of nausea and vomiting. More research is needed, and nicotine cannot currently be recommended as part of a multimodal pain management regime.


Iodine(III) Derivatives as Halogen Bonding Organocatalysts.
Hypervalent iodine(III) derivatives are known as versatile reagents in organic synthesis, but there is only one previous report on their use as Lewis acidic organocatalysts. Herein, we present first strong indications for the crucial role of halogen bonding in this kind of catalyses. To this end, the solvolysis of benzhydryl chloride and the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone served as benchmark reactions for halide abstraction and the activation of neutral compounds. Iodolium compounds (cyclic diaryl iodonium species) were used as activators or catalysts, and we were able to markedly reduce or completely switch off their activity by sterically blocking one or two of their electrophilic axes. Compared with previously established bidentate cationic halogen bond donors, the monodentate organoiodine derivatives used herein are at least similarly active (in the Diels-Alder reaction) or even decidedly more active (in benzhydryl chloride solvolysis).


Report on the Women in Physiology Symposium in IUPS 2009.
A symposium entitled "Women in Physiology" was held on 30 July 2009 during IUPS in Kyoto. Seven female researchers from five countries presented their views. This article includes the summary of each speaker's talk. Figures are not included here because they have been uploaded to the web site of Women Physiologists of Japan (WPJ) ( http://square.umin.ac.jp/wpj/ ) with the permission of each speaker. Please visit this internet site, download the files freely, and use them for presentations.


Structural analysis of the bacterial HPr kinase/phosphorylase V267F mutant gives insights into the allosteric regulation mechanism of this bifunctional enzyme.
The HPr kinase/phosphorylase (HPrK/P) is a bifunctional enzyme that controls the phosphorylation state of the phospho-carrier protein HPr, which regulates the utilization of carbon sources in Gram-positive bacteria. It uses ATP or pyrophosphate for the phosphorylation of serine 46 of HPr and inorganic phosphate for the dephosphorylation of Ser(P)-46-HPr via a phosphorolysis reaction. HPrK/P is a hexameric protein kinase of a new type with a catalytic core belonging to the family of nucleotide-binding protein with Walker A motif. It exhibits no structural similarity to eukaryotic protein kinases. So far, HPrK/P structures have shown the enzyme in its phosphorylase conformation. They permitted a detailed characterization of the phosphorolysis mechanism. In the absence of a structure with bound nucleotide, we used the V267F mutant enzyme to assess the kinase conformation. Indeed, the V267F replacement was found to cause an almost entire loss of the phosphorylase activity of Lactobacillus casei HPrK/P. In contrast, the kinase activity remained conserved. To elucidate the structural alterations leading to this drastic change of activity, the x-ray structure of the catalytic domain of L. casei HPrK/P-V267F was determined at 2.6A resolution. A comparison with the structure of the wild type enzyme showed that the mutation induces conformation changes compatible with the switch from phosphorylase to kinase function. Together with nucleotide binding fluorescence measurements, these results allowed us to decipher the cooperative behavior of the protein and to gain new insights into the allosteric regulation mechanism of HPrK/P.


Referral of high-risk pregnant mothers by trained traditional birth attendants in Buikwe County, Mukono District, Uganda.
Traditional birth attendants (TBAs) represent an important component of the healthcare system in resource-limited settings, and are present at 50% of deliveries in developing countries. While several studies have been carried out on the effectiveness of TBAs in reducing maternal morbidity and mortality, very little attention has been given to the needs assessment of TBAs within the environment they practice. We conducted a cross-sectional study among trained TBAs (TTBAs) in the Mukono District of Uganda with needs assessment as one of the aims of the survey. A total of 48 TTBAs within the age range of 19-80 years were interviewed. Knowledge of the TTBAs regarding obstetric cases requiring referral and years of experience gathered were satisfactory. Among the 38 referred mothers, one maternal and fetal death intra-partum were recorded, yielding a case fatality rate of 2.6%. The single most important need of TTBAs was transportation. On average, the distance between the residence and the workplace of a TTBA was 7 km, and lack of transportation hampered the actual transfer of cases to a higher level of care. To remedy this, we recommend the introduction of a practical, cheap and sustainable single-ambulance-multiple-cellular phone system to facilitate prompt referral of complicated obstetric cases within the entire Health District.


Synthesis of eicosa-2-trans-8,11,14-all cis-tetraenoic acid-3-14C and DL-3-hydroxy eicosa-8,11,14-all cis-trienoic acid-3-14C.
A general procedure for the synthesis of 2-trans polyenoic fatty acids and of dl-3-hydroxypolyenoic acids is described. The 2-trans acids are prepared by LiAlH(4) reduction of a suitable polyenoic fatty acid ester to the alcohol, formation of the tosylate, oxidation to the aldehyde, and Doebner condensation of the latter with malonic acid. The 3-hydroxy acids are obtained by reaction of the acyl chloride of a suitable polyenoic acid with the sodium enolate of methyl acetoacetate and sodium methoxide to give the 3-keto ester, the keto group of which is reduced with sodium borohydride to the alcohol. These procedures were applied to the synthesis of eicosa-2-trans-8, 11, 14-all cis-tetraenoic acid-3-(14)C and DL-3-hydroxy eicosa-8, 11, 14-trienoic acid-3-(14)C.


Tubulovillous Adenoma in the Bladder in a Dual Pancreas-Kidney Transplant Patient.
Background: A rare report of a tubulovillous adenoma arising in the setting of a dual pancreas-kidney transplant patient. Case Presentation: This adenoma was discovered in a 60-year-old male with a dual pancreas-kidney transplant that presented with urinary retention and gross hematuria. Management of this patient required both transurethral resection of the tumor as well as a laparotomy after recurrence. Follow-up with cystoscopy has shown no further recurrence of the tumor. Conclusion: This case adds to the few cases documented of adenomas arising in bladders augmented with gastrointestinal tract tissue. The tumor may reflect growth from donor duodenal graft tissue, however, the metaplasia of urothelial tissue cannot be fully ruled out. Based on this case, our understanding of these rare tumors and their clinical course is deepened.


EBV-associated lymphoid interstitial pneumonia in IBD patient: Case report and literature review.
Lymphoid interstitial pneumonia (LIP) is categorized as a rare form of interstitial lung disease. Most cases are associated with autoimmune disease. A 78-year-old male with Crohn's disease, presented with progressive dyspnea and dry cough for few weeks. The pathology of transbronchial lung biopsy was compatible with LIP and positive cells on EBER in situ hybridization. Blood EBV viral load was 85,715 copies/mL, compatible with EBV-associated LIP. All immunosuppressive agents were discontinued, but unfortunately the patient died due to hospital-acquired infections. In addition, we reviewed all reported cases of EBV-associated LIP in literature. To our knowledge, we report herein the first case of EBV-associated LIP in an IBD patient. We postulate that LIP was the consequence from EBV reactivation, probably due to immunosuppressive agents and/or IBD itself. The physician should aware of this disease when taking care of immunosuppressive patients who present with acute interstitial pneumonitis.


Type 2 diabetes and mammographic breast density among underserved women.
We conducted a study of women recruited at Meharry Medical College, a historically black medical school, to investigate the relationship between diabetes and mammographic breast density. A total of 476 women completed in-person interviews, body measurements, and full-field digital mammograms on a Hologic mammography unit from December 2011 to February 2014. Average percent breast density for the left and right breasts combined was estimated using Quantra, an automated algorithm for volumetric assessment of breast tissue. The prevalence of type 2 diabetes was determined by self-report. After adjustment for confounding variables, the mean percent breast density among premenopausal women with type 2 diabetes [[Formula: see text] 13.8 %, 95 % confidence interval (CI) 11.6-15.9] was nonsignificantly lower than that of women without type 2 diabetes ([Formula: see text] 15.9 %, 95 % CI 15.0-16.8) (p = 0.07); however, there was no association among postmenopausal women. The effect of type 2 diabetes in severely obese women (BMI ≥ 35) appeared to differ by menopausal status with a reduction in mean percent breast density in premenopausal women, but an increase in mean percent breast density in postmenopausal women which could have been due to chance. Confirmation of our findings in larger studies may assist in clarifying the role of the insulin signaling breast cancer pathway in women with high breast density.


[Symptom evaluation as an efficient diagnostic tool for upper abdominal diseases].
GERD and dyspepsia are common conditions, affecting approximately 25-40% of the general population. In the absence of alarm symptoms, the current recommended policy in young dyspeptic patients is a "test and treat" strategy for H. pylori. On the other hand, in GERD patients, a therapeutic trial with proton pump inhibitors (PPI) is the treatment of choice. This study aimed to create short and simple clinical algorithms, for the diagnosis and treatment of patients with upper gastrointestinal complaints. Data mining models and algorithms (neural networks, decision trees and logistic regression) were used to create a diagnostic symptom questionnaire to classify the patients into one of two diagnostic groups: GERD vs. non-GERD. The questionnaire was validated against endoscopic and clinical diagnoses of 132 patients in a cross-sectional study, and was designed to yield a "GERD score". The clinical and economical benefits of the new algorithm were evaluated in primary care clinics in Israel. The symptoms chosen for the diagnostic questionnaire were heartburn, acid regurgitation, sour oral taste, aggravation of symptoms after heavy meals, relief of symptoms by antacids, and nocturnal reflux. The use of the algorithm by primary care physicians improved clinical outcomes and reduced health resources consumption. This new short algorithm was found to be useful and easy to apply in clinical practice. The questionnaire can be also implemented in computerized medical systems.


Intestinal microbiota dysbiosis in acute kidney injury: novel insights into mechanisms and promising therapeutic strategies.
In recent years, the clinical impact of intestinal microbiota-kidney interaction has been emerging. Experimental evidence highlighted a bidirectional evolutionary correlation between intestinal microbiota and kidney diseases. Nonetheless, acute kidney injury (AKI) is still a global public health concern associated with high morbidity, mortality, healthcare costs, and limited efficient therapy. Several studies on the intestinal microbiome have improved the knowledge and treatment of AKI. Therefore, the present review outlines the concept of the gut-kidney axis and data about intestinal microbiota dysbiosis in AKI to improve the understanding of the mechanisms of the intestinal microbiome on the modification of kidney function and response to kidney injury. We also introduced the future directions and research areas, emphasizing the intervention approaches and recent research advances of intestinal microbiota dysbiosis during AKI, thereby providing a new perspective for future clinical trials.


The Effect of Information and Severity on Perception of Speakers With Adductor Spasmodic Dysphonia.
The purpose of this study was to examine the effect of severity of adductor spasmodic dysphonia (ADSD) and information about it on unfamiliar listeners' attitudes about speakers' personal characteristics, perceived vocal effort, and listener comfort on the basis of ratings of speech recordings. Fifteen women with ADSD and 5 controls provided speech samples. Forty-five unfamiliar listeners were randomized into 3 groups. Listeners in Group 1 received no information, listeners in Group 2 were told that some speakers had voice disorders or had no voice concerns, and listeners in Group 3 were provided diagnostic labels for each speaker and information about ADSD. Listeners then rated speech samples for attitudes, perceived vocal effort, and listener comfort. Speakers with ADSD were judged significantly worse than controls for attitudes related to "social desirability" and "intellect." There was no effect of severity on "personality" attributes. However, provision of a diagnostic label resulted in significantly more favorable personality ratings than when no label was provided. Perceived vocal effort and comfort became significantly more negative as ADSD severity increased. Finally, most listener ratings were unaffected by provision of additional information about ADSD. Listeners' perceptions about speakers with ADSD are difficult to change. Directions for counseling and public education need future study.


Buffer formulation affects the interaction between lysozyme and polymeric nanoparticles.
The effect of the buffer formulation in terms of buffer identity and ionic strength on the interaction between chicken egg lysozyme and carboxyl-modified polystyrene nanoparticles has been systematically studied. The time evolution of the fluorescence of a reporter molecule shows that lysozyme interacts with the nanoparticles in all the studied conditions. The interaction results in changes in protein conformation and decrease of the colloidal stability of nanoparticles. In absence of a background salt the rate of adsorption is affected mainly by the ionic strength of the buffer solution, although, specific buffer effects may contribute to a certain extent. The identity of the different buffer components does not significantly alter the dynamics of the process in presence of salt at constant ionic strength. However, an increase of ionic strength leads to slower processes indicating that the adsorption is affected by the presence of increasing number of ions in solution.


Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management.
Equine pituitary pars intermedia dysfunction (PPID) is a neurodegenerative disease of the hypothalamus, resulting in the loss of dopaminergic inhibition of pars intermedia. An oxidative stress injury of unknown etiology has been suggested to initiate the neurodegeneration. While hypertrichosis (formerly known as hirsutism) is considered pathognomic for advanced disease, the antemortem diagnosis of subclinical and early disease has continued to prove difficult. Numerous tests have been used with varying sensitivities and specificities. The overnight dexamethasone suppression test, originally documented to have 100% sensitivity and specificity in horses with advanced disease, has proven to be less valuable in identifying early disease. Basal plasma adrenocorticotropin concentrations have improved sensitivity and specificity when sampled during the autumn months, and α-melanocyte-stimulating hormone, while not yet commercially available, shows promise as a sensitive and specific single sample test. Recent advances in our knowledge include the strong association between laminitis and hyperinsulinemia, both common clinical signs associated with PPID. The pathogenesis of hyperinsulinemia, laminitis, and their association with this disease is a focus of current research. The dopamine agonist pergolide mesylate is still the mainstay of medical management, with studies on oral bioavailability, pharmacokinetics, and long-term survival rates now published.


Acupuncture inhibition of methamphetamine-induced behaviors, dopamine release and hyperthermia in the nucleus accumbens: mediation of group II mGluR.
Methamphetamine (METH) increases metabolic neuronal activity in the mesolimbic dopamine (DA) system and mediates the reinforcing effect. To explore the underlying mechanism of acupuncture intervention in reducing METH-induced behaviors, we investigated the effect of acupuncture on locomotor activity, ultrasonic vocalizations, extracellular DA release in the nucleus accumbens (NAcs) using fast-scan cyclic voltammetry and alterations of brain temperature (an indicator of local brain metabolic activity) produced by METH administration. When acupuncture was applied to HT7, but not TE4, both locomotor activity and 50-kHz ultrasonic vocalizations were suppressed in METH-treated rats. Acupuncture at HT7 attenuated the enhancement of electrically stimulated DA release in the NAc of METH-treated rats. Systemic injection of METH produced a sustained increase in NAc temperature, which was reversed by the DA D1 receptor antagonist SCH 23390 or acupuncture at HT7. Acupuncture inhibition of METH-induced NAc temperature was prevented by pre-treatment with a group II metabotropic glutamate receptors (mGluR2/3) antagonist EGLU into the NAc or mimicked by injection of an mGluR2/3 agonist DCG-IV into the NAc. These results suggest that acupuncture reduces extracellular DA release and metabolic neuronal activity in the NAc through activation of mGluR2/3 and suppresses METH-induced affective states and locomotor behavior.


Colon Metastasis From Microscopic Serous Carcinoma of the Fallopian Tube Fimbria Mimicking a Primary Colon Cancer.
Metastatic diseases rarely develop in the colorectum, and diagnosing colorectal metastasis by biopsy without history of a malignant tumor or clinical information of a primary tumor is challenging. A 65-year-old woman with a 6-month history of constipation and diarrhea was admitted to our hospital and diagnosed with rectosigmoid colonic micropapillary carcinoma. Low anterior resection was performed after neoadjuvant chemotherapy. Because the lipoleiomyoma in the uterus obstructed the operator's vision, total hysterectomy and bilateral salpingo-oophorectomy were performed. Examination of the colon and adnexa, together with immunohistochemical studies, revealed that the colonic tumor was actually serous carcinoma that had metastasized from the left fimbria of the fallopian tube. Retrospective immunohistochemical examination of the colon biopsy specimen suggested carcinoma with a Müllerian immunophenotype. When a colon biopsy reveals carcinoma with an invasive micropapillary pattern without a component of conventional tubular adenocarcinoma, immunohistochemical examination should be performed to rule out the possibility of metastasis.


Abnormal expression of CDK11p58 in prostate cancer.
CDK11p58 is one of the large families of p34cdc2-related kinases whose functions are linked with cell cycle progression, tumorigenesis and apoptotic signaling. Our previous investigation demonstrated that CDK11p58 repressed androgen receptor (AR) transcriptional activity and was involved in the negative regulation of AR function. CDK11p58 expression was examined in the prostate cancer tissues and adjacent tissues by IHC and qRT-PCR. Cell apoptosis was detected by flow cytometry. The metastasis of cancer cells was evaluated by the Transwell Assay. Finally we further investigated the underlying molecular mechanisms by examining expression levels of relevant proteins using western blot analysis. We found that both RNA and protein expression of CDK11p58 were low in prostate cancer tissues compared with its adjacent noncancerous tissues. CDK11p58 promoted the prostate cancer cell apoptosis and inhibited its metastasis in a kinase dependent way. And finally CDK11p58 could inhibit the metastasis of AR positive prostate cancer cells through inhibition of integrin β3 and MMP2. These data indicate that CDK11p58 is an anti-metastasis gene product in prostate cancer.


Effect of tuberculosis infection on mortality of HIV-infected patients in Northern Tanzania.
TB and HIV are public health problems, which have a synergistic effect to each other. Despite the decreasing burden of these two diseases they still make a significant contribution to mortality. Tanzania is among the 30 high TB and HIV burden countries. Routine data over 6 years from people living with HIV (PLHIV) attending health facilities in three regions of Northern Tanzania were analyzed, showing mortality trends from 2012 to 2017 for HIV and HIV/TB subpopulations. Poisson regression with frailty model adjusting for clustering at health facility level was used to analyze the data to determine mortality rate ratios (RR) and 95% confidence intervals (95%CI). Among all PLHIV the overall mortality rate was 28.4 (95% CI 27.6-29.2) deaths per 1000 person-years. For PLHIV with no evidence of TB the mortality rates was 26.2 (95% CI 25.4-27.0) per 1000 person-years, and for those with HIV/TB co-infection 57.8 (95% CI 55.6-62.3) per 1000 person-years. After adjusting for age, sex, residence, WHO stage, and bodyweight, PLHIV with TB co-infection had 40% higher mortality than those without TB (RR 1.4; 95% CI 1.24-1.67). Over the 6-year period mortality rates for HIV/TB patients were consistently higher than for PLHIV who have no TB. More efforts should be directed into improving nutritional status among HIV patients, as it has destructive interaction with TB for mortality. This will improve patients' body weight and CD4 counts which are protective against mortality. Among PLHIV attention should be given to those who are in WHO HIV stage 3 or 4 and having TB co-infection.


Approach to the Adolescent With Substance Use in the Acute Setting.
Psychoactive substance use during adolescence is an emerging challenge to the public health system due to the potential negative impact on the emotional, cognitive, social, physical and academic outcomes of adolescents. An increase in autonomy during adolescence, peer influence and willingness to experiment, lead to taking high-risk decisions subsequently prompting towards substance abuse and alcohol use. Substance use is heterogeneous among adolescents, which differs with availability, perceptions of use and specific drug usage. In adolescents' substance abuse, beyond emergency care, brief counselling with psychosocial assessment and follow up are recommended for successful management. The article reviews the common substances used by adolescents, types of presentations, clinical evaluation of patients and their background, laboratory testing, emergency management and follow up for long-term management.


Cinacalcet to prevent parathyrotoxic crises in hypercalcaemic patients awaiting parathyroidectomy.
Primary hyperparathyroidism is the third most common endocrine disorder. Hypercalcaemia exceeding 3 mmol/l is a major risk factor for parathyrotoxic crises, and management of patients at risk remains a medical challenge. The authors recently managed three such patients referred for severe nephrolithiasis. All had severe hypercalcaemia (at least 3 mmol/l). Instead of the usual management, which involves hospitalisation in an intensive care environment (for about 5-7 days) for rehydration and infusion of intravenous bisphosphonates, followed by emergency parathyroidectomy, the three patients received ambulatory cinacalcet (not an approved indication), 30 mg twice a day. The serum calcium normalised in two cases and declined to a safe level in the third case, allowing minimally invasive parathyroidectomy to be performed at a date chosen according to the patients' and surgeon's respective schedules. The authors consider that cinacalcet may benefit severely hypercalcaemic patients awaiting surgery for primary hyperparathyroidism.


[Chronic hemodialysis-related porphyria/pseudoporphyria].
In a considerable proportion of the patients with chronic renal failure, skin changes resembling porphyria cutanea tarda (PCT) develop some months to years after the onset of maintenance hemodialysis. This can be either real PCT, or secondary PCT, or PCT-like bullous dermatosis. In a minor proportion, real PCT can be diagnosed. In such cases, elevated total porphyrin levels with a predominance of uro- (I > III) and heptacarboxyl porphyrins (III > I) can be measured in the plasma (also in the urine, if not anuric), and fecal (perhaps urinary as well) isocoproporphyrin can be detected. The activity of the hepatic uroporphyrinogen decarboxylase (UD) is decreased in every type of PCT; in PCT-II, also that of the erythrocyte UD. In a higher proportion, secondary PCT (pseudo-PCT) develops. In this group, porphyrins are accumulated in the plasma due to the unsatisfactory renal function. Uro and hepta are the dominant fractions here as well, but alteration in the ratio of the uro isomers or the presence of isocoproporphyrin can not be expected. The UD activity is probably normal in every tissue. In 1% to 18% of the cases, PCT-like bullous dermatoses develop, but porphyrins are at normal levels in all compartments. The phototoxic agent here is other than porphyrin (e.g. nalidixic acid, furosemide, tetracycline, etc., or unknown). The authors review the knowledge on chronic hemodialysis-related PCT or the PCT-like bullous dermatoses: development of the above-mentioned conditions, clinical and morphological and biochemical features, difficulties in diagnosis, or the possibilities in therapy.


Analysis of homogeneity of treatment effect in adaptive multicenter clinical trials.
In this paper, an exact test for analyzing the homogeneity of treatment effect in adaptive multicenter clinical trials is proposed. Extensive simulation studies are performed to investigate the large sample behavior of a commonly used test statistic for testing homogeneity of treatment effect. When the sample size in each center is large relative to the number of centers, the asymptotic null distribution of the test statistic is reasonable. On the other hand, when the data are relatively sparse, the proposed exact test should be used to incorporate the adaptive nature of the design.


Simulation of the rate of transfer of antibiotic resistance between Escherichia coli strains cultured under well controlled environmental conditions.
It was demonstrated that the tetracycline resistance plasmid in Escherichia coli resembling K-12 23:06 containing the E. coli plasmid DM0133 could be transferred to tetracycline sensitive E. coli K-12 MG1655 YFP. The sensitive recipient strain has a slight metabolic advantage in continuous fermentation in absence of tetracycline pressure and as a result the numbers of the resistant recipient strain increase during fermentation. In presence of tetracycline pressure the sensitive strain is eliminated, but when it acquires tetracycline resistance the strain has still the same metabolic advantage as its sensitive parent strain in absence of tetracycline. Here a model will be shown that could explain the rate of transformation of a sensitive into a resistant recipient strain and its subsequent growth during continuous fermentation. According to the model the probability of formation of mutants would be much higher at the dilution rate of 0.09 compared to 0.28, whereas the growth of mutants would be much faster at high dilution rate. The growth model shows how the recipient mutants and the donor cells behave in relation to the dilution rate and the number of mutants. Apart from a deterministic model describing the growth rate of both the donor strain and the resistant recipient strain a stochastic model was developed that is particularly useful when low numbers of mutants are formed.


Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1.
The goal was to analyze the clinical responses to enzyme replacement therapy with alglucerase or imiglucerase in a large international cohort of children with Gaucher disease type 1. Anonymized data from 884 children in the International Collaborative Gaucher Group Gaucher Registry were analyzed to determine the effects of long-term enzyme replacement therapy with alglucerase or imiglucerase on hematologic and visceral manifestations, linear growth, and skeletal disease. The parameters measured were hemoglobin levels, platelet counts, spleen and liver volumes, z scores for height and bone mineral density, and reports of bone pain and bone crises. The median height z score for the study population was -1.4 at baseline. After 8 years of treatment, the median height approximated the median value for the normal population. Anemia, although not severe, was present in >50% of patients at baseline and resolved for all patients after 8 years of treatment. More than 50% of patients had platelet counts of <100000 platelets per mm3 at baseline, but >95% had platelet counts above this level after 8 years of treatment. Liver and spleen volumes decreased over 8 years of treatment. The mean bone mineral density z score was -0.34 at baseline, and values normalized within 6.6 years of treatment. Seventeen percent of patients reported a bone crisis before treatment and in the first 2 years of treatment, but no bone crises were reported after 2 years of enzyme replacement therapy. Few patients (2.5%) without bone crises before enzyme replacement therapy had a crisis after the start of treatment. These longitudinal data quantitate the benefits of continuous enzyme replacement therapy with alglucerase/imiglucerase for children with Gaucher disease type 1. Within 8 years of enzyme replacement therapy, most clinical parameters studied became normal or nearly normal.


Community-acquired methicillin-resistant Staphylococcus aureus carriage rate and antimicrobial susceptibility in a tertiary center, Iran.
This study was aimed to determine frequency and antimicrobial susceptibility of Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) among colonized patients in outpatient status. A total of 2000 nasal nares specimens were collected and inoculated on mannitol salt agar. MRSAs were identified based on mannitol positivity and coagulase test followed by cefoxitin disc diffusion test. Antimicrobial susceptibility of MRSA isolates was performed by E-test method for vancomycin and doxycycline as well as disc diffusion method for sulfamethoxazole-trimethoprim (SMX-TMP), erythromycin, linezolid, and clindamycin. D-test was performed for detection of inducible resistance to clindamycin. Overall, nasal carrier rate of S. aureus and CA-MRSA was estimated 22% and 1.25%, respectively. Out of the 440 S. aureus isolates, 25 isolates were MRSA. All were susceptible to vancomycin and linezolid, and susceptibility rates to SMX-TMP, erythromycin, levofloxacin, doxycycline, and clindamycin were 68%, 44%, 48%, 40% and 44%, respectively; furthermore, 28.5% of resistant isolates to erythromycin had inducible resistance to clindamycin. It seems susceptibility to clindamycin and SMX-TMP, recommended agents for empirical treatment of suspected CA-MRSA, are not promising. Vancomycin and linezolid are effective and reliable antibiotics for the treatment of S. aureus infections.


Smoking-Related "Interstitial" Lung Disease.
Emphysema, respiratory bronchiolitis, desquamative interstitial pneumonia, pulmonary Langerhans' cell histiocytosis, small-airway injury including submucosal and adventitial fibrosis, increased bronchus-associated lymphoid tissue, and small artery/arteriolar wall thickening are recognized histologic findings in cigarette smokers. It has only recently been acknowledged that the range of lung injury from cigarette smoke is wider than generally accepted, in particular, there is increasing recognition that fibrosis of alveolar walls occurs in smokers. To review the literature that describes the range of histologic findings in cigarette smokers and that links cigarette smoke exposure to the development of alveolar wall fibrosis. Relevant peer-reviewed literature indexed in PubMed (National Library of Medicine) form the basis of this review. Smokers demonstrate a wide range of lung injury at biopsy that defies simple placement within single categories, and the current categories do not adequately take into account the importance of alveolar wall and airway fibrosis.


Reversible Polymer-Chain Modification: Ring-Opening and Closing of Polylactone.
A reversible polymer modification involving structural changes of the polymer chains was accomplished for the copolymer of CO2 and butadiene. The bicyclic structures were opened by hydrolysis and aminolysis reactions of the lactone moiety. For the hydrolysis product, the ring-closing of the ring-opened product was achieved by simply heating without any reagents or solvents. Nuclear magnetic resonance and matrix assisted laser desorption/ionization time-of-flight analyses and size-exclusion chromatography measurement of the polymer before ring-opening and after ring-closure suggested the retention of the polymer structure as well as the molecular weight and polydispersity during the reversible processes, proving that the modification can be performed without significant macroscopic changes of the polymer structure.


Optic flow signals in extrastriate area MST: comparison of perceptual and neuronal sensitivity.
The medial superior temporal area of extrastriate cortex (MST) contains signals selective for nonuniform patterns of motion often termed "optic flow." The presence of such tuning, however, does not necessarily imply involvement in perception. To quantify the relationship between these selective neuronal signals and the perception of optic flow, we designed a discrimination task that allowed us to simultaneously record neuronal and behavioral sensitivities to near-threshold optic flow stimuli tailored to MST cells' preferences. In this two-alternative forced-choice task, we controlled the salience of globally opposite patterns (e.g., expansion and contraction) by varying the coherence of the motion. Using these stimuli, we could both relate the sensitivity of neuronal signals in MST to the animal's behavioral sensitivity and also measure trial-by-trial correlation between neuronal signals and behavioral choices. Neurons in MST showed a wide range of sensitivities to these complex motion stimuli. Many neurons had sensitivities equal or superior to the monkey's threshold. On the other hand, trial-by-trial correlation between neuronal discharge and choice ("choice probability") was weak or nonexistent in our data. Together, these results lead us to conclude that MST contains sufficient information for threshold judgments of optic flow; however, the role of MST activity in optic flow discriminations may be less direct than in other visual motion tasks previously described by other laboratories.


Impact of the De-Alloying Kinetics and Alloy Microstructure on the Final Morphology of De-Alloyed Meso-Porous Metal Films.
Nano-textured porous metal materials present unique surface properties due to their enhanced surface energy with potential applications in sensing, molecular separation and catalysis. In this paper, commercial alloy foils, including brass (Cu85Zn15 and Cu70Zn30) and white gold (Au50Ag50) foils have been chemically de-alloyed to form nano-porous thin films. The impact of the initial alloy micro-structure and number of phases, as well as chemical de-alloying (DA) parameters, including etchant concentration, time and solution temperature on the final nano-porous thin film morphology and properties were investigated by electron microscopy (EM). Furthermore, the penetration depth of the pores across the alloys were evaluated through the preparation of cross sections by focus ion beam (FIB) milling. It is demonstrated that ordered pores ranging between 100 nm and 600 nm in diameter and 2-5 μm in depth can be successfully formed for the range of materials tested. The microstructure of the foils were obtained by electron back-scattered diffraction (EBSD) and linked to development of pits across the material thickness and surface during DA. The role of selective etching of both noble and sacrificial metal phases of the alloy were discussed in light of the competitive surface etching across the range of microstructures and materials tested.


Latest Canadian Consensus Conference on the Diagnosis and Treatment of Dementia: What's in It for Primary Care?
In 2020, the fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD5) published up-to-date recommendations for the clinical management of persons living with dementia (PLWD) and their caregivers. During the CCCDTD5 meetings, a list of recommendations for dementia care was compiled. With the aid of family physicians and the Canadian Consortium on Neurodegeneration in Aging, we selected the most relevant CCCDTD5 recommendations for primary care and tailored and summarized them in the present manuscript to facilitate their reference and use. These recommendations focus on (a) risk reduction, (b) screening and diagnosis, (c) deprescription of dementia medications, and (d) non-pharmacological interventions. The development of recommendations for the ongoing management of dementia is an iterative process as new evidence on interventions for dementia is published. These recommendations are important in the primary care setting as the entry point for PLWD into the health system.


The role of the scapula in athletic shoulder function.
The exact role and the function of the scapula are misunderstood in many clinical situations. This lack of awareness often translates into incomplete evaluation and diagnosis of shoulder problems. In addition, scapular rehabilitation is often ignored. Recent research, however, has demonstrated a pivotal role for the scapula in shoulder function, shoulder injury, and shoulder rehabilitation. This knowledge will help the physician to provide more comprehensive care for the athlete. This "Current Concepts" review will address the anatomy of the scapula, the roles that the scapula plays in overhead throwing and serving activities, the normal biomechanics of the scapula, abnormal biomechanics and physiology of the scapula, how the scapula may function in injuries that occur around the shoulder, and treatment and rehabilitation of scapular problems.


Double Empirical Bayes Testing.
Analyzing data from large-scale, multi-experiment studies requires scientists to both analyze each experiment and to assess the results as a whole. In this article, we develop double empirical Bayes testing (DEBT), an empirical Bayes method for analyzing multi-experiment studies when many covariates are gathered per experiment. DEBT is a two-stage method: in the first stage, it reports which experiments yielded significant outcomes; in the second stage, it hypothesizes which covariates drive the experimental significance. In both of its stages, DEBT builds on Efron (2008), which lays out an elegant empirical Bayes approach to testing. DEBT enhances this framework by learning a series of black box predictive models to boost power and control the false discovery rate (FDR). In Stage 1, it uses a deep neural network prior to report which experiments yielded significant outcomes. In Stage 2, it uses an empirical Bayes version of the knockoff filter (Candes et al., 2018) to select covariates that have significant predictive power of Stage-1 significance. In both simulated and real data, DEBT increases the proportion of discovered significant outcomes and selects more features when signals are weak. In a real study of cancer cell lines, DEBT selects a robust set of biologically-plausible genomic drivers of drug sensitivity and resistance in cancer.


Structural effects of phenolic acids on the transepithelial transport of fluorescein in caco-2 cell monolayers.
The structural specificity of the monocarboxylic acid transporter (MCT) for the transport of phenolic acids was investigated by measuring the inhibitory effect on the fluorescein transport in Caco-2 cell monolayers. Although most of the monohydroxylated derivatives had an inhibitory effect, the di- and tri-hydroxylated ones did not. The methoxylated derivatives were more inhibitory than the hydroxylated ones in all the meta-substituted derivatives, suggesting that meta-hydroxylation of the substrate would decrease the affinity for MCT.


Targeting Bacillus cereus cells: increasing efficiency of antimicrobials by the bornylpossessing 2(5Н)-furanone derivative.
Among a variety of antimicrobial compounds, the derivatives of 2(5H)-furanone exhibit different effects on Firmicutes and Proteobacteria. While inhibiting quorum-dependent biofilm formation and virulence factor expression by Gram-negative bacteria through specific interference with the AI-2 signaling pathways, these compounds demonstrate bactericidal effects against Gram-positive bacteria. Here we report that 3,4-dichloro-5(S)-[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy]-2(5H)-furanone designed as F123 inhibits growth and biofilm formation by the food-poisoning bacterium Bacillus cereus at 8 μg/ ml and kills bacteria at 16 μg/ml. While the growth of Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis were also inhibited at 8-16 μg/ml of F123, no bactericidal effect on these strains was observed at concentrations up to 128 μg/ml, suggesting pronounced specificity of F123 for B. cereus. In a checker-board assay F123 increased the efficacy of amikacin, gentamicin and benzalkonium chloride against B. cereus with medians of fractional inhibitory concentration index of 0.38, 0.56 and 0.56, respectively. Moreover, the number of viable B. cereus cells in biofilm was reduced by more than 3 orders of magnitude at 64 μg/ml of F123, suggesting its chemotype as a promising enhancer for specific treatment of B. cereus-associated topical infections, including biofilm-embedded bacteria.


Night Shift Work and Risk of Depression: Meta-analysis of Observational Studies.
This study aimed to assess whether night shift work is associated with the risk of depression by using a meta-analysis of observational studies. We searched PubMed and EMBASE in August, 2016 to locate eligible studies and investigated the association between night shift work and the risk of depression, reporting outcome measures with adjusted odds ratios (ORs) or relative risks (RRs) and 95% confidence intervals (CIs). In the meta-analysis of a total of 11 observational studies with 9 cross-sectional study, 1 longitudinal study, and 1 cohort study, night shift work was significantly associated with an increased risk of depression (OR/RR, 1.43; 95% CI, 1.24-1.64; I² = 78.0%). Also, subgroup meta-analyses by gender, night shift work duration, type of occupation, continent, and type of publication showed that night shift work was consistently associated with the increased risk of depression. The current meta-analysis suggests that night shift work is associated with the increased risk of depression. However, further large prospective cohort studies are needed to confirm this association.