Is the problem list in the eye of the beholder? An exploration of consistency across physicians.
Quantify the variability of patients' problem lists - in terms of the number, type, and ordering of problems - across multiple physicians and assess physicians' criteria for organizing and ranking diagnoses. In an experimental setting, 32 primary care physicians generated and ordered problem lists for three identical complex internal medicine cases expressed as detailed 2- to 4-page abstracts and subsequently expressed their criteria for ordering items in the list. We studied variability in problem list length. We modified a previously validated rank-based similarity measure, with range of zero to one, to quantify agreement between pairs of lists and calculate a single consensus problem list that maximizes agreement with each physician. Physicians' reasoning for the ordering of the problem lists was recorded. Subjects' problem lists were highly variable. The median problem list length was 8 (range: 3-14) for Case A, 10 (range: 4-20) for Case B, and 7 (range: 3-13) for Case C. The median indices of agreement - taking into account the length, content, and order of lists - over all possible physician pairings was 0.479, 0.371, 0.509, for Cases A, B, and C, respectively. The median agreements between the physicians' lists and the consensus list for each case were 0.683, 0.581, and 0.697 (for Cases A, B, and C, respectively).Out of a possible 1488 pairings, 2 lists were identical. Physicians most frequently ranked problem list items based on their acuity and immediate threat to health. The problem list is a physician's mental model of a patient's health status. These mental models were found to vary significantly between physicians, raising questions about whether problem lists created by individual physicians can serve their intended purpose to improve care coordination.


In-Home Pulmonary Telerehabilitation for Patients with Chronic Obstructive Pulmonary Disease: A Pre-experimental Study on Effectiveness, Satisfaction, and Adherence.
Pulmonary rehabilitation (PR) has proven effective in improving exercise tolerance and quality of life in patients with chronic obstructive pulmonary disease (COPD). In Canada, however, there are insufficient rehabilitation services. New strategies such as telerehabilitation must be deployed to increase accessibility. This study aims to investigate the effect of telerehabilitation on exercise tolerance and quality of life and to document patient satisfaction and adherence. Twenty-six patients with moderate to very severe COPD participated in this pre-/postintervention study. They received 15 in-home teletreatment sessions over 8 weeks via videoconference from a service center to their home. Education was provided via self-learning health capsules. Assessments were carried out twice before (T0 and T1; 8 weeks apart) and immediately after the intervention (T2). Primary outcome measures were changes in exercise tolerance (6-min walk test [6MWT] and cycle endurance test [CET]) and quality of life (Chronic Respiratory Questionnaire [CRQ]). There were significant improvements between pre- and postintervention (T2-T1) on the 6MWT (32 m; p<0.001), CET (41 s; p=0.005), and three of four CRQ domains (dyspnea [p<0.001], fatigue [p=0.002], and emotion [p=0.002]). Improvements in the CET and fatigue during the 8-week intervention period were greater than changes over 8 weeks of maturation (T1-T0) (p=0.004 and 0.02, respectively). Participants' satisfaction and adherence rate with telerehabilitation were very high. Using telehealth technology to deliver in-home PR is a feasible and practical solution for patients with moderate to very severe COPD. The telerehabilitation program was associated with beneficial effects on exercise tolerance and quality of life and was well received by users.


The role of the inhibition of glutathione-S-transferase in the protective mechanisms of ischemic postconditioning.
The antioxidant glutathione-S-transferase (GST) is a crucial determinant of the development of ischaemic-reperfusion (I/R) injury, and plays a pivotal role in the regulation of the mitogen activated protein kinase (MAPK) pathways involved in stress response and apoptosis. The aim of this study was to investigate whether inhibition of GST can abolish the benefit of ischaemic postconditioning (IPoC). A neonatal rat cardiomyocyte cell culture was prepared and divided into 6 groups: (I) control group without treatment; (II) cells exposed to simulated I/R; (III) simulated I/R (sI/R) with IPoC; (IV) ethacrynic acid (EA) alone; (V) sI/R with EA; and (VI) sI/R and IPoC together with EA. Viability of the cells was measured by MTT assay, the quantity of apoptotic cells was assessed by flow cytometry following annexin V-FITC - propidium-iodide double staining. The activation of JNK, p38, ERK/p42-p44 MAPKs, and GSK-3β protein kinase was determined by flow-cytometric assay. GST inhibition markedly increased the apoptosis and decreased the cell viability despite IPoC. The protective effect of IPoC was lost in GST-inhibited groups for all MAPKs and GSK-3β. GST activity is required for the survival of cultured cardiomyocytes under stress conditions. GST inhibition was associated with differential activation of MAP and the protein kinases regulating these pathways in the process of ischaemic postconditioning.


Monophosphoryl lipid A enhances both humoral and cell-mediated immune responses to DNA vaccination against human immunodeficiency virus type 1.
To enhance immunity induced by DNA vaccination against human immunodeficiency virus type 1 (HIV-1), we evaluated the efficacy of monophosphoryl lipid A (MPL), an adjuvant of bacterial origin. BALB/c mice were intramuscularly injected with immunogenic DNA, encoding the env and rev genes of the HIV-1(IIIB) strain, formulated with MPL dissolved in different vehicles (MPL in stable emulsion and MPL in aqueous formulation). The sera from mice immunized with the two preparations of MPL revealed 2(6) to 2(9) times higher HIV-1-specific immunoglobulin G (IgG) titers than the sera from mice immunized without MPL. In virus neutralization tests for HIV-1(IIIB), by p24 assay and antifusion assay of infected MOLT-4 cells, MPL tends to elicit antibody more protective than antibody elicited without adjuvant. MPL also elicited stronger delayed-type hypersensitivity and cytotoxic-T-lymphocyte activity against HIV-1(IIIB) compared to DNA alone. HIV-1-specific IgG subclass analysis showed that MPL tends to facilitate IgG2a production, suggesting enhancement of a predominant T-helper-type-1 response, and this enhancement may help to facilitate protective-antibody induction. Furthermore, a chloramphenicol acetyltransferase (CAT) assay was employed to determine whether MPL affected the gene expression process. Interestingly, both MPL preparations reduced CAT activity in the muscle injected with CAT expression vector but increased anti-CAT antibody production. These results indicate that MPL acts as an effective adjuvant for immunogenic DNA injection despite reduced expression of encoding protein in muscle. We conclude that MPL has a strong adjuvant effect on DNA vaccination against HIV-1.


Monitoring of Low-Intensity Exposures via Luminescent Bioassays of Different Complexity: Cells, Enzyme Reactions, and Fluorescent Proteins.
The current paper reviews the applications of luminescence bioassays for monitoring the results of low-intensity exposures which produce a stimulative effect. The impacts of radioactivity of different types (alpha, beta, and gamma) and bioactive compounds (humic substances and fullerenols) are under consideration. Bioassays based on luminous marine bacteria, their enzymes, and fluorescent coelenteramide-containing proteins were used to compare the results of the low-intensity exposures at the cellular, biochemical, and physicochemical levels, respectively. High rates of luminescence response can provide (1) a proper number of experimental results under comparable conditions and, therefore, proper statistical processing, with this being highly important for "noisy" low-intensity exposures; and (2) non-genetic, i.e., biochemical and physicochemical mechanisms of cellular response for short-term exposures. The results of cellular exposures were discussed in terms of the hormesis concept, which implies low-dose stimulation and high-dose inhibition of physiological functions. Dependencies of the luminescence response on the exposure time or intensity (radionuclide concentration/gamma radiation dose rate, concentration of the bioactive compounds) were analyzed and compared for bioassays of different organization levels.


Population-based age group specific annual incidence rates of symptomatic age-related macular degeneration.
To study the population-based annual incidence rates of exudative, dry and all cases of symptomatic age-related macular degeneration (AMD) in different age and sex groups. This is a one year, prospective, population-based study on all consecutive new patients with AMD in the hospital district of Central Finland. The diagnosis was confirmed in all patients with slit lamp biomicroscopy, optical coherence tomography (OCT) using a Spectralis HRA + OCT device, and the Heidelberg Eye Explorer 188.8.131.52 program. Fluorescein angiograms were taken when needed. The population-based annual incidence rates of all cases of symptomatic AMD increased from 0.03% (95% CI, 0.01-0.05%) in the age group 50-59 years to 0.82% (95% CI, 0.55-1.09%) in the age group 85-89 years and were 0.2% (95% CI, 0.17-0.24%) in exudative, 0.11% (95% CI, 0.09-0.14%) in dry, and 0.32% (95% CI, 0.28-0.36%) in all cases of AMD in the age group 60 years and older. During the next 20 years in Central Finland the population-based annual incidence rates can be estimated to increase to 0.27% (95% CI, 0.24-0.30%) in exudative, to 0.13% (95% CI, 0.11-0.15%) in dry, and to 0.41% (95% CI, 0.37-0.45%) in all cases of AMD in the age group 60 years and older. The population-based annual incidence of AMD did not show statistically significant differences between males and females (p>0.1). The population-based age-group specific annual incidence rates of symptomatic AMD of this study may help to plan health care provision for patients of AMD.


The trigger-information-response model: Exploring health literacy during the first six months following a kidney transplantation.
The main objective of this study was to explore how kidney transplant recipients find, understand, and use health information, and make decisions about their health-also known as health literacy. Kidney transplant recipients must take an active part in their health following the transplantation, since a new organ requires new medication and focus on lifestyle to prevent side-effects and signs of organ rejection. Consequently, it is of major clinical relevance to explore how kidney transplant recipients understand and relate to health literacy. Ten kidney transplant recipients were interviewed at three weeks and again at six months post-transplantation. Design and analysis were inspired by constructivist grounded theory. The results of the study are presented through a model consisting of three phases: the trigger phase, the information phase, and the response phase. The participants were influenced by context and personal factors as they moved between three phases, as information seekers, recipients, and sharers. This study illustrates health literacy as an active process. It gives new insight into what motivates kidney recipients to find, share, and receive information, and how a hierarchy of resources is built and used.


Functional imaging of the thoracic outlet syndrome in an open MR scanner.
Symptoms due to thoracic outlet syndrome may present only in abduction, a position that cannot be investigated in conventional MR scanners. Therefore, this study was initiated to test MRI in an open magnet as a method for diagnosis of thoracic outlet syndrome. Ten volunteers and 7 patients with a clinical suspicion of thoracic outlet syndrome were investigated at 0.5 T in an open MR scanner. Sagittal 3D SPGR acquisitions were made in 0 and 90 degrees abduction. In the patients, a similar data set was also obtained in maximal abduction. To assess compression, the minimum distance between the first rib and the clavicle, measured in a sagittal plane, was determined. In the neutral position, no significant difference was found between patients and controls. In 90 degrees abduction, the patients had significantly smaller distance between rib and clavicle than the controls (14 vs 29 mm; p < 0.01). On coronal reformatted images, the compression of the brachial plexus could often be visualised in abduction. Functional MR examination seems to be a useful diagnostic tool in thoracic outlet syndrome. Examination in abduction, which is feasible in an open scanner, is essential for the diagnosis.


Nucleotide sequence analysis of the proviral genome of avian myelocytomatosis virus (MC29).
The nucleotide sequence of the integrated proviral genome of avian myelocytomatosis virus (MC29) coding for gag-myc protein has been determined. By comparison of this nucleotide sequence with the helper virus as well as the c-myc region, it was possible to localize the junction points between helper viral and v-myc sequences. These studies demonstrate that (i) the large terminal repeat sequence of MC29 is very similar to that of Rous sarcoma virus, (ii) the viral genome has suffered extensive deletions in the gag, pol, and env genes, (iii) the gag region can code for p19, p10, and part of p27, (iv) the recombination between viral and cellular sequences occurred in the coding region of p27 such that the open reading frame extends for an additional stretch of 1,266 base pairs, resulting in a gag-myc hybrid protein, (v) the open reading frame terminated within the v-myc region 300 bases upstream of v-myc-helper viral junction, and (vi) the v-myc helper-viral junction at the 3' end occurred in the middle of env gene, rendering it defective.


Dyskerin is required for tumor cell growth through mechanisms that are independent of its role in telomerase and only partially related to its function in precursor rRNA processing.
Dyskerin is an essential nucleolar protein required for the biogenesis of ribonucleoproteins that incorporate H/ACA RNAs. Through binding to specific H/ACA RNAs, dyskerin exerts most of its influence in the cell. To that end, dyskerin is a core component of the telomerase complex and is required for normal telomere maintenance. Dyskerin is also required for post-transcriptional processing of precursor rRNA. Germline dyskerin mutations increase cancer susceptibility. Conversely, wild-type dyskerin is usually over-expressed and not mutated in sporadic cancers. However, the contributions of dyskerin to sporadic tumorigenesis are unknown. Described herein, we demonstrate that acute loss of dyskerin function by RNA interference significantly reduced steady-state levels of H/ACA RNAs, disrupted the morphology and inhibited anchorage-independent growth of telomerase-positive and telomerase-negative human cell lines. Unexpectedly, dyskerin depletion only transiently delayed rRNA maturation but with no appreciable effect on the levels of total 18S or 28S rRNA. Instead, while rRNA processing defects typically trigger p53-dependent G1 arrest, dyskerin-depleted cells accumulated in G2/M by a p53-independent mechanism, and this was associated with an accumulation of aberrant mitotic figures that were characterized by multi-polar spindles. Telomerase activity and the rate of rRNA processing are typically increased during neoplasia. However, our cumulative findings indicate that dyskerin contributes to tumor cell growth through mechanisms which do not require the presence of cellular telomerase activity, and which may be only partially dependent upon the protein's role in rRNA processing. These data also reinforce the notion that loss and gain of dyskerin function may play important roles in tumorigenesis.


Comparative study of the innervation patterns of the hyobranchial musculature in three iguanian lizards: Sceloporus undulatus, Pseudotrapelus sinaitus, and Chamaeleo jacksonii.
The neuroanatomy and musculature of the hyobranchial system was studied in three species of iguanian lizards: Sceloporus undulatus, Pseudotrapelus sinaitus, and Chamaeleo jacksonii. The goal of this study was to describe and compare the innervation and arrangement of the hyobranchial musculature in the context of its function during tongue protrusion. A comparison of the hyobranchial innervation patterns revealed a relatively conserved innervation pattern in S. undulatus and P. sinaitus, and a modified version of this basic layout in C. jacksonii. All three species show anastomoses between sensory neurons of the trigeminal nerve and motor neurons of the hypoglossal nerve, suggesting that feedback may be important in coordinating tongue, jaw, and hyoid movements. The hyobranchial musculature of S. undulatus is very similar to that of P. sinaitus; however, there are minor differences, including the presence of an M. genioglossus internus (GGI) muscle in S. undulatus. Further differences are found mainly in functional aspects of the hyobranchial musculature, such as changes in the muscle lengths and the origins and insertions of the muscles. In C. jacksonii the hyobranchial system is comprised of largely the same components, but it has become highly modified compared to the other two species. Based on the innervation and morphological data gathered here, we propose a revision of the terminology for the hyobranchial musculature in iguanian lizards.


Towards equity: a qualitative exploration of the implementation and impact of a digital educational intervention for pharmacy professionals in England.
Patients belonging to marginalised (medically under-served) groups experience problems with medicines (i.e. non-adherence, side effects) and poorer health outcomes largely due to inequitable access to healthcare (arising from poor governance, cultural exclusion etc.). In order to promote service equity and outcomes for patients, the focus of this paper is to explore the implementation and impact of a new co-produced digital educational intervention on one National Health Service (NHS) funded community pharmacy medicines management service. Semi-structured interviews with a total of 32 participants. This included a purposive sample of 22 community pharmacy professionals, (16 pharmacists and 6 pharmacy support staff) all who offered the medicine management service. In order to obtain a fuller picture of the barriers to learning, five professionals who were unable to complete the learning were also included. Ten patients (from a marginalised group) who had received the service (as a result of the digital educational intervention) were also interviewed. Drawing on an interpretative analysis, Normalisation Process Theory (NPT) was used as a theoretical framework. Three themes are explored. The first is how the digital learning intervention was implemented and applied. Despite being well received, pharmacists found it challenging completing and cascading the learning due to organisational constraints (e.g. lack of time, workload). Using the four NPT constructs (coherence, cognitive participation, collective action and reflexive monitoring) the second theme exposes the impact of the learning and the organisational process of 'normalisation'. Professional reflective accounts revealed instances where inequitable access to health services were evident. Those completing the intervention felt more aware, capable and better equipped to engage with the needs of patients who were from a marginalised group. Operationally there was minimal structural change in service delivery constraining translation of learning to practice. The impact on patients, explored in our final theme, revealed that they experience significant disadvantage and problems with their medicines. The medication review was welcomed and the discussion with the pharmacist was helpful in addressing their medicine-related concerns. The co-produced digital educational intervention increases pharmacy professionals' awareness and motivation to engage with marginalised groups. However structural barriers often hindered translation into practice. Patients reported significant health and medicine challenges that were going unnoticed. They welcomed the additional support the medication review offered. Policy makers and employers should better enable and facilitate ways for pharmacy professionals to better engage with marginalised groups. The impact of the educational intervention on patients' health and medicines management could be substantial if supported and promoted effectively.


Regulation of class II gene expression in a murine pre-B cell line.
Class II major histocompatibility complex (MHC) gene expression has been studied in an Abelson virus-transformed pre-B cell line R8, and its Ia-negative variant R8205. These variant cells contained barely detectable levels of RNA specific for all class II genes, including the nonpolymorphic invariant chain gene (Ii), and did not express cell surface Ia. Fusion of this murine Ia-negative cell line to the human Ia-positive Raji cell produced an interspecies hybridoma that expressed the murine Ia. These data are further evidence for the existence of trans-acting factors that can regulate class II gene expression. Furthermore, the T cell-derived lymphokine B cell stimulatory factor 1 (BSF-1) induced expression of class II genes in the R8205 cells. Exposure of R8205 cells to an antibody that has been shown to mimic BSF-1 activity on normal B cells also resulted in expression of class II genes. These data demonstrate that three distinct signals--a lymphokine, an alloantibody binding to membrane structures, and an interspecies trans-acting factor--can induce expression of class II genes.


The lysin motif receptor-like kinase (LysM-RLK) CERK1 is a major chitin-binding protein in Arabidopsis thaliana and subject to chitin-induced phosphorylation.
Plants detect potential pathogens by sensing microbe-associated molecular patterns via pattern recognition receptors. In the dicot model plant Arabidopsis, the lysin motif (LysM)-containing chitin elicitor receptor kinase 1 (CERK1) has been shown to be essential for perception of the fungal cell wall component chitin and for resistance to fungal pathogens. Recent in vitro studies with CERK1 protein expressed heterologously in yeast suggested direct chitin binding activity. Here we show in an affinity purification approach that CERK1 is a major chitin-binding protein of Arabidopsis cells, along with several known and putative chitinases. The ectodomain of CERK1 harbors three distinct LysM domains with potential ligand binding capacity. We demonstrate that the CERK1 ectodomain binds chitin and partially deacetylated chitosan directly without any requirement for interacting proteins and that all three LysM domains are necessary for chitin binding. Ligand-induced phosphorylation events are a general feature of animal and plant signal transduction pathways. Our studies show that chitin, chitin oligomers, and chitosan rapidly induce in vivo phosphorylation of CERK1 at multiple residues in the juxtamembrane and kinase domain. Functional analyses with a kinase dead variant provide evidence that kinase activity of CERK1 is required for its chitin-dependent in vivo phosphorylation, as well as for early defense responses and downstream signaling. Collectively, our data suggest that in Arabidopsis, CERK1 is a major chitin, chitosan, and chito-oligomer binding component and that chitin signaling depends on CERK1 post-translational modification and kinase activity.


p21CDKN1A Regulates the Binding of Poly(ADP-Ribose) Polymerase-1 to DNA Repair Intermediates.
The cell cycle inhibitor p21CDKN1A was previously found to interact directly with DNA nick-sensor poly(ADP-ribose) polymerase-1 (PARP-1) and to promote base excision repair (BER). However, the molecular mechanism responsible for this BER-related association of p21 with PARP-1 remains to be clarified. In this study we investigate the capability of p21 to influence PARP-1 binding to DNA repair intermediates in a reconstituted BER system in vitro. Using model photoreactive BER substrates containing single-strand breaks, we found that full-length recombinant GST-tagged p21 but not a C-terminal domain truncated form of p21 was able to stimulate the PARP-1 binding to BER intermediates with no significant influence on the catalytic activity of PARP-1. In addition, we investigate whether the activation of PARP-1 through poly(ADP-ribose) (PAR) synthesis, is required for its interaction with p21. We have found that in human fibroblasts and in HeLa cells treated with the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the interaction of p21 with PARP-1 was greatly dependent on PAR synthesis. In fact, an anti-PAR antibody was able to co-immunoprecipitate p21 and PARP-1 from extracts of MNNG-treated cells, while blocking PAR synthesis with the PARP-1 inhibitor Olaparib, drastically reduced the amount of p21 co-immunoprecipitated by a PARP-1 antibody. Our results provide the first evidence that p21 can stimulate the binding of PARP-1 to DNA repair intermediates, and that this cooperation requires PAR synthesis.


The neural generators of the mismatch responses to Mandarin lexical tones: an MEG study.
The present magnetoencephalography study used the cortically constrained minimum-norm estimates of human brain activity to elucidate functional roles of neural generators for detecting different magnitudes of lexical tones changes. A multiple-deviant oddball paradigm was used in which the syllable "yi" with a low-dipping tone (T3) was the common standard sound and the same syllable with a high-level tone (T1) or a high-rising tone (T2) were the large and small deviant sounds, respectively. The data revealed a larger magnetic mismatch field (MMNm) for large deviant in the left hemisphere. The source analysis also confirmed that the MMNm to lexical tone changes was generated in bilateral superior temporal gyri and only the large deviant revealed left lateralization. A set of frontal generators was activated at a later time and revealed differential sensitivities to the degree of deviance. The left anterior insula, the right anterior cingulate cortex, and the right ventral orbital frontal cortex were activated when detecting a large deviant, whereas the right frontal-opercular region was sensitive to the small deviant. These frontal generators were thought to be associated with various top-down mechanisms for attentional modulation. The time frequency (TF) analysis showed that large deviants yielded large theta band (5-7Hz) activity over the left anterior scalp and the left central scalp, while small deviants yielded large alpha band activity (9-11Hz) over the posterior scalp. The results of TF analyses implied that mechanisms of working memory and functional inhibition involved in the processes of acoustic change detection.


A Web-Based Computer-Tailored Alcohol Prevention Program for Adolescents: Cost-Effectiveness and Intersectoral Costs and Benefits.
Preventing excessive alcohol use among adolescents is important not only to foster individual and public health, but also to reduce alcohol-related costs inside and outside the health care sector. Computer tailoring can be both effective and cost-effective for working with many lifestyle behaviors, yet the available information on the cost-effectiveness of computer tailoring for reducing alcohol use by adolescents is limited as is information on the costs and benefits pertaining to sectors outside the health care sector, also known as intersectoral costs and benefits (ICBs). The aim was to assess the cost-effectiveness of a Web-based computer-tailored intervention for reducing alcohol use and binge drinking by adolescents from a health care perspective (excluding ICBs) and from a societal perspective (including ICBs). Data used were from the Alcoholic Alert study, a cluster randomized controlled trial with randomization at the level of schools into two conditions. Participants either played a game with tailored feedback on alcohol awareness after the baseline assessment (intervention condition) or received care as usual (CAU), meaning that they had the opportunity to play the game subsequent to the final measurement (waiting list control condition). Data were recorded at baseline (T0=January/February 2014) and after 4 months (T1=May/June 2014) and were used to calculate incremental cost-effectiveness ratios (ICERs), both from a health care perspective and a societal perspective. Stochastic uncertainty in the data was dealt with by using nonparametric bootstraps (5000 simulated replications). Additional sensitivity analyses were conducted based on excluding cost outliers. Subgroup cost-effectiveness analyses were conducted based on several background variables, including gender, age, educational level, religion, and ethnicity. From both the health care perspective and the societal perspective for both outcome measures, the intervention was more costly and more effective in comparison with CAU. ICERs differed for both perspectives, namely €40 and €79 from the health care perspective to €62 and €144 for the societal perspective per incremental reduction of one glass of alcohol per week and one binge drinking occasion per 30 days, respectively. Subgroup analyses showed, from both perspectives and for both outcome measures, that the intervention was cost-effective for older adolescents (aged 17-19 years) and those at a lower educational level and, from a health care perspective, the male and nonreligious adolescent subgroups. Computer-tailored feedback could be a cost-effective way to target alcohol use and binge drinking among adolescents. Including ICBs in the economic evaluation had an impact on the cost-effectiveness results of the analysis. It could be worthwhile to aim the intervention specifically at specific subgroups. Nederlands Trial Register: NTR4048; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4048 (Archived by Webcite at http://www.webcitation.org/6c7omN8wG).


The transcript level of interleukin-6 in the cartilage of idiopathic osteoarthritis of knee.
The mRNA level for interleukin-6 (IL-6) is an important marker of osteoarthritis (OA). The present study aimed to investigate the level of IL-6 mRNA in the cartilage of OA knee while comparing it to the normal cartilage obtained from the same patient. A total of 21 patients who underwent total knee replacement were recruited for this study. Sectioning of the destructive cartilage was performed in the medial part of the proximal tibiofemoral cartilage. The unaffected lateral part of the knee in the same patient, served as a control. The mRNA level for IL-6 was assessed using LightCycler 2.0 quantitative real-time polymerase chain reaction (qRT-PCR). actin mRNA was used as an endogenous control. Twelve out of 21 patients (57.1%) exhibited up regulation of IL-6 mRNA in the OA cartilage as compared to the normal cartilage. The rest of the patients (42.9%) showed down regulation of IL-6 mRNA. The statistical analysis showed there was insignificant level of IL-6 mRNA in the OA (1.91 +/- 0.45) as compared to the normal cartilage (1.13 +/- 0.44) (p > 0.05). The inter-individual variation in the level of IL-6 mRNA in the cartilage of idiopathic knee was in accordance with previous findings. These observations suggest IL-6 could also act as a catabolic agent in some patients or its expression might be influenced by other cytokines.


The K+ uptake regulator TrkA controls membrane potential, pH homeostasis and multidrug susceptibility in Mycobacterium smegmatis.
Rifampicin is an important first-line antibiotic for the treatment of mycobacterial infections. Although most rifampicin-resistant strains arise through mutations in the rpoB gene in bacteria, a proportion of such strains show no rpoB mutations. This suggests that alternative mechanisms are responsible for rifampicin resistance. We have constructed and analysed a library of 11, 000 Mycobacterium smegmatis insertion mutants to find other possible rifampicin-resistance determinants. We found that disruption of trkA, a putative regulator of K(+) uptake, leads to increased rifampicin resistance. Our data indicate that TrkA-mediated K(+) uptake is essential for maintenance of the M. smegmatis growth rate, its pH homeostasis and membrane potential. In addition to increased rifampicin resistance, inactivation of trkA confers resistance to other hydrophobic agents, such as novobiocin, as well as increased susceptibility to isoniazid and positively charged aminoglycosides. Our results suggest that trkA is a general regulator of antibiotic susceptibility, and the changes in the multidrug susceptibility/resistance pattern detected in the trkA mutant are associated with membrane hyperpolarization. This study sheds light on the role of ion transport activity in intrinsic and acquired antibiotic resistance in mycobacteria.


Borderline personality disorder symptoms and aggression: A within-person process model.
Theoretical and empirical work suggests that aggression in those with borderline personality disorder (BPD) occurs primarily in the context of emotional reactivity, especially anger and shame, in response to perceived rejection. Using intensive repeated measures, we examined a within-person process model in which perceived rejection predicts increases in aggressive urges and behaviors via increases in negative affect (indirect effect) and in which BPD symptoms exacerbate this process (moderated mediation). Participants were 117 emerging adult women (ages 18-24) with recent histories of aggressive behavior who were recruited from a community-based longitudinal study of at-risk youth. Personality disorder symptoms were assessed by semistructured clinical interview, and aggressive urges, threats, and behaviors were measured in daily life during a 3-week ecological momentary assessment protocol. Multilevel path models revealed that within-person increases in perceived rejection predicted increases in negative affect, especially in women with greater BPD symptoms. In turn, increases in negative affect predicted increased likelihood of aggressive urges or behaviors. Further analysis revealed that BPD symptoms predicted greater anger and shame reactivity to perceived rejection, but not to criticism or insult. Additionally, only anger was associated with increases in aggression after controlling for other negative emotions. Whereas BPD symptoms exacerbated the link between perceived rejection and aggression via increases in negative affect (particularly anger), this process was attenuated in women with greater antisocial personality disorder symptoms. These findings suggest that anger reactivity to perceived rejection is one unique pathway, distinct from antisocial personality disorder, by which BPD symptoms increase risk for aggression. (PsycINFO Database Record


Efficacy and safety of oral Chinese patent medicines in the treatment of coronary heart disease combined with hyperlipidemia: a systematic review and network meta-analysis of 78 trials.
To evaluate the clinical efficacy and safety of commonly used oral Chinese patent medicines for the treatment of coronary heart disease combined with hyperlipidemia in clinical practice through a network meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, Wanfang, VIP, SinoMed, and CNKI databases were searched for all published randomized controlled trials (RCTs) on the treatment of coronary heart disease combined with hyperlipidemia using Chinese patent medicines. NoteExpress software was used to screen the literature obtained from the databases according to the inclusion and exclusion criteria. The Cochrane risk of bias assessment tool was used to evaluate the quality of the included studies. A network meta-analysis was performed using R 4.2.1. Subgroup analyses of outcome indicators were made based on conventional treatment (CT) methods. The incidence of adverse events in the included RCTs was statistically analyzed. A funnel plot was drawn using RevMan 5.4.1 software for the assessment of bias in the total clinical effectiveness rate. Finally, the quality of evidence for interventions with statistically significant differences was evaluated using the GRADE system. A total of 78 RCTs were included, involving 7,955 cases and 8 types of Chinese patent medicines, which were Tongxinluo Capsule, Naoxintong Capsule, Compound Danshen Dripping Pill, Shexiangbaoxin Pill, Songling Xuemaikang Capsule, Xuezhikang Capsule, Yindan Xinnaotong Capsule, and Zhibitai Capsule. A total of 24 RCTs reported the incidence of adverse events, but no statistically significant difference in the incidence of adverse events was found between the experimental and control groups in each study (P > 0.05). There was no obvious publication bias in all studies, but the overall quality of evidence in the included RCTs was low. Comparison of different intervention measures showed that Naoxintong Capsule + CT improved the cardiac index and cardiac output, and lowered the low-density lipoprotein cholesterol and total cholesterol levels. Tongxinluo Capsule + CT raised high-density lipoprotein cholesterol levels and reduced triglyceride levels. Xuezhikang Capsule + CT improved the total clinical effectiveness rate. Subgroup analyses showed that differences in CT did not cause heterogeneity in the results. Compared with the use of CT alone, the combined use of Chinese patent medicines with CT can effectively improve the symptoms in patients with both coronary heart disease and hyperlipidemia.


From Experience to Memory: On the Robustness of the Peak-and-End-Rule for Complex, Heterogeneous Experiences.
Memory forms the input for future behavior. Therefore, how individuals remember a certain experience may be just as important as the experience itself. The peak-and-end-rule (PE-rule) postulates that remembered experiences are best predicted by the peak emotional valence and the emotional valence at the end of an experience in the here and now. The PE-rule, however, has mostly been assessed in experimental paradigms that induce relatively simple, one-dimensional experiences (e.g., experienced pain in a clinical setting). This hampers generalizations of the PE-rule to the experiences in everyday life. This paper evaluates the generalizability of the PE-rule to more complex and heterogeneous experiences by examining the PE-rule in a virtual reality (VR) experience, as VR combines improved ecological validity with rigorous experimental control. Findings indicate that for more complex and heterogeneous experiences, peak and end emotional valence are inferior to other measures (such as averaged valence and arousal ratings over the entire experiential episode) in predicting remembered experience. These findings suggest that the PE-rule cannot be generalized to ecologically more valid experiential episodes.


Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina.
MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs, and removal of Dicer has been shown to disrupt many developmental processes. In this study, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knock-out mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at postnatal day 16, which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic electroretinogram (ERG) responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer-depleted retinas showed a decrease in several miRNAs. The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.


Childhood body fatness and the risk of epithelial ovarian cancer: A population-based case-control study in Montreal, Canada.
To assess the association between childhood body fatness and epithelial ovarian cancer (EOC), and whether this association differs by type of EOC. Using data from a population-based case-control study (497 cases and 902 controls) in Montreal, Canada conducted 2011-2016, we examined the association between childhood body fatness and EOC, overall and separately for invasive vs. borderline EOCs. A figure rating scale was used to measure body fatness at ages 5 and 10. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Quantitative bias analyses were conducted to assess the impact of exposure misclassification and non-participation. The aOR (95% CI) of overall EOC for high vs. low body fatness was 1.07 (0.85-1.34) at age 5 and 1.28 (0.98-1.68) at age 10. The associations were stronger for invasive EOC, specifically the endometrioid histological type. For borderline cancers, the aORs were below the null value with wide confidence intervals. Bias analyses did not reveal a strong influence of non-participation. Non-differential exposure misclassification may have biased aORs towards the null for invasive cancers but did not appear to have an appreciable influence on the aORs for borderline cancers. Childhood body fatness may be a risk factor for invasive EOC in later adult life. Our study highlights the potential importance of examining early life factors for a comprehensive understanding of EOC development.


Sinonasal NUT carcinoma: A consecutive case series and systematic review.
Sinonasal NUT carcinoma is an extremely rare, lethal malignancy with limited literature. A case series was conduction of all patients with sinonasal NUT carcinoma at a single institution between 2010 and 2022. Survival and associated were evaluated. A systematic review of the literature was performed. In 12 patients, followed for a median of 1.5 years, the median overall survival (OS) and disease-specific survival (DSS) were both 14.6 months. Patients with maxillary sinus tumors were 91% more likely to survive (hazard ratio [HR]: 0.094, 95% confidence interval [CI]: 0.011-0.78, p = 0.011). Patients with higher-stage disease stage had worse OS (stage IVb-c vs. III-IVa, p = 0.05). All three patients who were alive with no evidence of disease received induction chemotherapy. For patients with sinonasal NUT carcinoma, the median survival was 15 months but better with lower-stage and maxillary tumors. Induction chemotherapy may be beneficial.


Contemporary clinical trials in pancreatic cancer immunotherapy targeting PD-1 and PD-L1.
Pancreatic cancer (PC) is a major gastrointestinal cancer in terms of worldwide incidence and mortality. Despite advances in diagnostic and treatment modalities, the mortality of PC is still a serious concern in both sexes. Immune therapy using inhibitors of immune checkpoints, especially inhibitors of programmed cell death protein 1/programmed cell death ligand-1(PD-1/PD-L1), offer huge benefits to cancer patients. This review describes an up-to-date information on the role of PD-1 and PD-L1 in the development of immune tolerance in PC alongside the current clinical trials and the known outcomes citing the available literature. We also included the details on PD-1/PD-L1-mediated signalling in maintenance of PC stem cells and metastasis. We reviewed the critical information on safety, tolerance, and efficacy of clinically important regimens of PD-1/PD-L1 blocking agents and targeted therapeutics. This review elucidates the underlying mechanisms of PD-1/PD-L1 alliance in tolerance of the immune system, maintenance of stem cells, and metastasis promotion as well as design regimens with high safety and excellent tolerability and efficacy for management of PC in advanced stages.


Implicit and explicit evaluation: FMRI correlates of valence, emotional intensity, and control in the processing of attitudes.
Previous work suggests that explicit and implicit evaluations (good-bad) involve somewhat different neural circuits that process different dimensions such as valence, emotional intensity, and complexity. To better understand these differences, we used functional magnetic resonance imaging to identify brain regions that respond differentially to such dimensions depending on whether or not an explicit evaluation is required. Participants made either good-bad judgments (evaluative) or abstract-concrete judgments (not explicitly evaluative) about socially relevant concepts (e. g., ''murder,'' ''happiness,'' ''abortion,'' ''welfare''). After scanning, participants rated the concepts for goodness, badness, emotional intensity, and how much they tried to control their evaluation of the concept. Amygdala activation correlated with emotional intensity and right insula activation correlated with valence in both tasks, indicating that these aspects of stimuli were processed by these areas regardless of intention. In contrast, for the explicitly evaluative good-bad task only, activity in the anterior cingulate, frontal pole, and lateral areas of the orbital frontal cortex correlated with ratings of control, which in turn were correlated with a measure of ambivalence. These results highlight that evaluations are the consequence of complex circuits that vary depending on task demands.


Support in the community for people with dementia and their carers: a comparative outcome study of specialist mental health service interventions.
This study aimed to evaluate outcomes for carers receiving the Admiral Nurse Service, a specialist mental health nursing service for carers of people with dementia. In contrast to many community mental health teams, it works primarily with the caregiver, focuses exclusively on dementia and offers continuing involvement, throughout the caregiving career, including emotional support, provision of information and coordination of practical support. 104 carers of people with dementia who were interviewed as soon as possible after being referred to a number of Admiral Nurse (AN) services or conventional services in neighbouring areas, and who were re-interviewed eight months later, form the sample (43 AN; 61 comparison). There were no significant differences between groups, controlling for initial score, on the primary outcome measure at follow-up, the 28-item General Health Questionnaire (GHQ) or its sub-scales, apart from anxiety and insomnia, where outcome was better for the AN group (p = 0.038). Follow-up GHQ scores were associated with ratings of past and current relationship quality. There were no differences in survival in the community between the groups. Both conventional and AN services are associated with lower distress scores over an eight-month period. Outcome for people with dementia (in terms of institutional placement) is no worse in the AN group, despite the carer focus. Some support is provided for a model of dementia-specialist service which engages with the caregiver and continues involvement for as long as is required, rather than simply carrying out an assessment and referring the person back to social services or primary care.


Spondylolysis. A skeletal investigation of two population groups.
The lumbar spines of 485 skeletons of adult South African "Whites" and "Blacks" of both sexes were examined to determine the incidence and morphology of defects in the pars interarticularis. The overall incidence was 3.5%, without significant variation between races and sexes. The incidence of lumbar spina bifida in the whole sample was 1.9%, but was 11.8% in those skeletons with spondylolysis. Some instances of unilateral spondylolysis demonstrated obvious callus formation, suggesting a capability for normal repair. It is possible that the defects in bilateral cases represent established non-union of fractures of the pars interarticularis resulting from excessive mobility, and are not due to dysplasia of bone. It is noted, for the first time, that the superior facets of affected vertebrae are abnormally enlarged, and that the inferior facets of the separate neural arch are characteristically elliptical.


Case Report: Melioidosis-Related Severe Cutaneous Features of Erythema Nodosum in a Thai Child.
Erythema nodosum (EN) is characterized by rapidly developing, painful, erythematous subcutaneous nodules, most of which are located in the pretibial areas. This cutaneous finding can be caused by a variety of conditions, however Burkholderia pseudomallei is rarely the cause. This particular patient presented with a high-grade fever with characteristic EN on both pretibial areas. All of the typical EN causes were investigated, but the findings were all negative. The lesions progressed to severe hemorrhagic bleb features, and because the patient resided in Northeast Thailand, a melioidosis-endemic region, testing for B. pseudomallei was performed. Because a high level of melioidosis serology of more than 1:10,240 was detected, melioidosis therapy was started. At the 12-week follow-up after melioidosis therapy, the titer had declined to 1:1,280, indicating that melioidosis-related severe, cutaneous EN symptoms were the most likely diagnosis in this patient. We discovered a case of EN with severe hemorrhagic bleb features as a unique clinical manifestation of melioidosis. When a patient resides in an endemic area, B. pseudomallei should always be considered as a possible causative organism.


ENT Referral From Emergency Department During COVID-19: A Single-Center Experience.
COVID-19 pandemic transformed the health system response worldwide. The aim of this study is to report changes about numbers and reason for ENT consultations in emergency department (ED) during COVID-19 pandemic comparing with those occurred the previous year (2019). Data about patients admitted to adult and pediatric ED were collected from March 1 to May 31, 2019 and 2020. Patients referred for urgency from general practitioners were excluded from the study. Global ED admission (except for dyspnea or COVID-19-related symptoms) dramatically decreased during pandemic (-50.9% among adults and -71.4% among pediatrics). At the same time, ENT consultancy significantly reduced too, by 71.5% (P < .01) among adults and 45.1% (P < .01) for pediatrics. Among adults, it was reported a statistically significant decrease in consultation for ear problems (-88.5%, P = .0146). Reduction in ENT referral for bone fracture (-40%, P = .059), vertigo (-77.8%, P = .637), and tonsillitis (-87.5%, P = .688) was consistent, but not significant. Among pediatric patients, it was observed an increase by 25% about foreign bodies (12 vs 15, P < .01). A reduction in numbers of consults for ear problem (-90.8%; P = .045), epistaxis (-80%; P = .196), and nasal fracture (-70%; P = .36) was also observed. Fear of infection and the forced lock down caused a significant decrease in the number of ED accesses and in ENT consultancy. These data may suggest that some ED referral usually could be deferred, but on the other hand, pandemic will cause a great diagnostic delay.


Diabetes modulation of the myocardial infarction-acute kidney injury axis.
As there is cross talk in functions of the heart and kidney, acute or chronic injury in one of the two organs provokes adaptive and/or maladaptive responses in both organs, leading to cardiorenal syndrome (CRS). Acute kidney injury (AKI) induced by acute heart failure is referred to as type 1 CRS, and a frequent cause of this type of CRS is acute myocardial infarction (AMI). Diabetes mellitus increases the risk of AMI and also the risk of AKI of various causes. However, there have been only a few studies in which animal models of diabetes were used to examine how diabetes modulates AMI-induced AKI. In this review, we summarize findings regarding the mechanisms of type 1 CRS and the impact of diabetes on both AMI and renal susceptibility to AKI and we discuss mechanisms by which diabetes modulates AMI-induced AKI. Hemodynamic alterations induced by AMI could be augmented by diabetes via its detrimental effect on infarct size and contractile function of the noninfarcted region in the heart. Diabetes increases susceptibility of renal cells to hypoxia and oxidative stress by modulation of signaling pathways that regulate cell survival and autophagy. Recent studies have shown that diabetes mellitus even at early stage of cardiomyopathy/nephropathy predisposes the kidney to AMI-induced AKI, in which activation of Toll-like receptors and reactive oxygen species derived from NADPH oxidases are involved. Further analysis of cross talk between diabetic cardiomyopathy and diabetic kidney disease is necessary for obtaining a more comprehensive understanding of modulation of the AMI-AKI axis by diabetes.


[Morphogenesis of the chick embryo foot as studied by Janus green B-induced malformations].
Janus green was injected into the amniotic sac of 6-5-day-old chick embryos at a single dose of 8-5 or 15 mug; the dye causes respectively 55 and 82% malformations of the feet. Toe are affected by partial or total soft tissue syndactyly, hypophalangy and infrequently by hyperphalangy. Lateral toes are more severely and more frequently affected by syndactyly and hypophalangy than medium ones. Hyperphalangy is found exclusively in toes I and II and causes the formation of one excess phalanx at most. Syndactylous toes are joined by an overdeveloped digital membrane. Hypophalangic toes have a truncated (non-pointed) distal tip. Two phalanges are lacking at most. These malformations are due to two distinct phases of the Janus green action. The first one, which is early and fast, inhibits interdigital programmed cell death, causing in term the non-regression of the interdigital membranes and thus syndactyly. The second one, which is late and slow, blocks the apical growth; this leads to hypophalangy.


Maternal liver damage delays meiotic resumption in bovine oocytes through impairment of signalling cascades originated from low p38MAPK activity in cumulus cells.
The main objective of the present study is to investigate the molecular mechanism underlying the delay in progression of nuclear maturation in oocytes derived from cows with damaged livers (DL cows), which was previously reported. In present study, delayed progression of nuclear maturation of oocytes derived from DL cows relative to oocytes derived from cows with healthy livers (HL cows) was accompanied by low maturation promoting factor (MPF) activity (0.43 fold, p < 0.05). When cumulus cells were removed from cumulus-oocyte complexes and the denuded oocytes were cultured, there was no difference in the progression of nuclear maturation between the two liver conditions. In addition, gap junctional communication (GJC) between the oocyte and cumulus cells was higher in DL cows than in HL cows at 3 and 7 h of in vitro maturation (IVM) (p < 0.05). Supplementation of IVM medium with epidermal growth factor (EGF) increased the ratio of germinal vesicle breakdown (GVBD) of oocytes derived from DL cows to the level seen in oocytes derived from HL cows. Additionally, the level of p38MAPK phosphorylation at 0 h of IVM was significantly lower in cumulus cells derived from DL cows than in cumulus cells derived from HL cows (HL cows, 53.5%; DL cows, 28.9%; p < 0.05). Thus, a low level of p38MAPK phosphorylation in cumulus cells induced slow GJC closure between oocyte and cumulus cells, which resulted in slow meiotic maturation of oocytes derived from DL cows.


Jaw-muscle activity changes after the induction of osteoarthrosis in the temporomandibular joint by mechanical loading.
To examine the effect of mechanical loading on the induction of temporomandibular joint osteoarthrosis (TMJ OA). Mechanical stress was applied to the rat TMJ by forced jaw opening of 3 hours a day for 5 days. The electromyographic (EMG) activity of the masseter and digastric muscles was continuously monitored by radio-telemetry. It was characterized by the total time each muscle was active (duty time), the number of bursts, and the average burst length. For histologic analysis, rats were sacrificed before, immediately after, and 3 weeks after the period of forced jaw opening. The condylar cartilage revealed OA-like lesions with a decrease in the number of chondrocytes immediately after forced jaw opening. Three weeks later, the OA-like lesions were repaired to some extent. After the forced jaw opening, the duty time of the masseter increased, whereas the duty time of the digastric decreased significantly (P < .01) at the 5% activity level. Three weeks later, the masseter duty time had decreased and the digastric duty time had slightly increased, returning to the levels observed before forced jaw opening. These results suggest that mechanical overloading of the TMJ induced OA-like lesions with a simultaneous influence on jaw muscle activity, especially at the low activity level. This might imply that muscle activity adapted to reduce the effects of (forced) joint overloading.


A Nationwide Survey of UK Oncologists' Views on the Choice of Radiotherapy Regime for the Reconstructed Chest Wall in Breast Cancer Patients.
Aims. This paper describes a UK survey of the choice of radiotherapy regime for the reconstructed chest wall in breast cancer patients. Questions focused on which fractionation regime consultants choose, their reasons for this, whether the type of reconstruction influences their choice, and whether bolus is used in patients who have undergone immediate reconstructive surgery. Materials and Methods. Between July 2014 and July 2015 a survey was sent by email to UK consultant radiation oncologists treating breast cancer. Results. The response rate was 73%. 67% of respondents use 40 Gray (Gy) in 15 fractions, with 22% using 50 Gy in 25 fractions and 7% using other regimes. For 90% of consultants the type of reconstruction did not influence their decision regarding choice of fractionation. 83% of respondents do not usually use a bolus for chest wall radiotherapy in patients who have had immediate reconstructive surgery. Conclusions. This survey illustrates there is variation in practice in the management of patients with breast cancer who have undergone immediate reconstructive surgery in the UK. There is a need for further research to determine which fractionation regime is optimal, whether the type of surgery is relevant, and whether bolus should be added.


Relaxation times, rheology, and finite size effects for non-Brownian disks in two dimensions.
We carry out overdamped simulations in a simple model of jamming-a collection of bidisperse soft core frictionless disks in two dimensions-with the aim to explore the finite size dependence of different quantities, both the relaxation time obtained from the relaxation of the energy and the pressure equivalent of the shear viscosity. The motivation for the paper is the observation [Nishikawa et al., J. Stat. Phys. 182, 37 (2021)0022-471510.1007/s10955-021-02710-8] that there are finite size effects in the relaxation time, τ, that give problems in the determination of the critical divergence, and the claim that this is due to a finite size dependence, τ∼lnN, which makes τ an ill-defined quantity. Beside analyses to determine the relaxation time for the whole system we determine particle relaxation times which allow us to determine both histograms of particle relaxation times and the average particle relaxation times-two quantities that are very useful for the analyses. The starting configurations for the relaxation simulations are of two different kinds-completely random or taken from steady shearing simulations-and we find that the difference between these two cases are bigger than previously noted and that the observed problems in the determination of the critical divergence obtained when starting from random configurations are not present when instead starting the relaxations from shearing configurations. We also argue that the the effect that causes the lnN dependence is not as problematic as asserted. When it comes to the finite size dependence of the pressure equivalent of the shear viscosity we find that our data don't give support for the claimed strong finite size dependence, but also that the finite size dependence is at odds with what one would normally expect for a system with a diverging correlation length, and that this calls for an alternative understanding of the phenomenon of shear-driven jamming.


Brain maturation in the first 3 months of life, measured by electroencephalogram: A comparison between preterm and term-born infants.
Preterm infants are at risk for altered brain maturation resulting in neurodevelopmental impairments. Topographical analysis of high-density electroencephalogram during sleep matches underlying brain maturation. Using such an EEG mapping approach could identify preterm infants at risk early in life. 20 preterm (gestational age < 32 weeks) and 20 term-born infants (gestational age > 37 weeks) were recorded by 18-channel daytime sleep-EEG at term age (GA 40 weeks for preterm and 2-3 days after birth for term infants) and 3 months (corrected age for preterm infants). Preterm infant's power spectrum at term age is immature, leveling off with term infants at 3 months of age. Topographical distribution of maximal power density however, reveals qualitative differences between the groups until 3 months of age. Preterm infants exhibit more temporal than central activation at term age and more occipital than central activation at 3 months of age. Moreover, being less mature at term age predicts being less mature at 3 months of age. Topographical analysis of sleep EEG reveals changes in brain maturation between term and preterm infants early in life. In future, automated analysis tools using topographical power distribution could help identify preterm infants at risk early in life.


Implication of AMP-activated protein kinase in transient receptor potential vanilloid type 1-mediated activation of endothelial nitric oxide synthase.
We investigated whether AMP-activated protein kinase (AMPK), a multi-functional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in Matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E deficient (ApoE(-/-)) mice was abrogated in TRPV1-deficient ApoE(-/-) mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.


Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister-chromatid cohesion.
Genetic studies in yeast and Drosophila have uncovered a conserved acetyltransferase involved in sister-chromatid cohesion. Here, we described the two human orthologues, previously named EFO1/ESCO1 and EFO2/ESCO2. Similar to their yeast (Eco1/Ctf7 and Eso1) and fly (deco) counterparts, both proteins feature a conserved C-terminal domain consisting of a H2C2 zinc finger motif and an acetyltransferase domain that is able to catalyze autoacetylation reaction in vitro. However, no similarity can be detected outside of the conserved domain. RNA interference depletion experiment revealed that EFO1/ESCO1 and EFO2/ESCO2 were not redundant and that both were required for proper sister-chromatid cohesion. The difference between EFO1 and EFO2 also is reflected in their cell cycle regulation. In mitosis, EFO1 is phosphorylated, whereas EFO2 is degraded. Furthermore, both proteins associate with chromosomes, and the chromosome binding depends on the diverse N-terminal domains. We propose that EFO1 and EFO2 are targeted to different chromosome structures to help establish or maintain sister-chromatid cohesion.


Enhanced Lignanamide Absorption and Antioxidative Effect of Extruded Hempseed (Cannabis sativa L.) Hull in Caco-2 Intestinal Cell Culture.
Despite the latest pursuit to discover novel phenolic compounds in hempseed and its biological properties, it remains a mystery whether they can be absorbed in the human body. Extrusion treatment and extraction of the free phenolic fraction significantly (p < 0.05) improved human Caco-2 intestinal cell absorption for hempseed hull lignanamides including cannabisin B (Papp value of 1.35 × 10-5 ± 1.0 × 10-6) as compared to the bound fraction of raw hull (Papp value of 2.82 × 10-6 ± 5.2 × 10-7). Co-supplementation of the flavonoid naringenin (20 μM) further improved these absorption rates. Higher cellular antioxidant activity was observed in the free extraction fractions. Treatment with the free phenolic fraction of extruded hempseed hull (100 mg/mL) alleviated tert-butyl hydroperoxide's (25 μM) negative effects on cell viability, intracellular malondialdehyde levels, apoptosis induction, glutathione S-transferase, and glutathione levels. RNA-sequencing with the limma method unveiled a total of 2795 differentially expressed genes in 21 day-old Caco-2 intestinal cells, suggesting the changes in cell metabolism after exposure to extruded hempseed hull extract. This study could promote the utilization of extrusion technology to improve the absorption and antioxidant capacities of bioactive phenolics in plant food processing byproducts.


Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014).
Death with graft function remains an important cause of graft loss among kidney transplant recipients (KTRs). Little is known about the trend of specific causes of death in KTRs in recent years. We analyzed United States Renal Data System data (1996-2014) to determine 1- and 10-year all-cause and cause-specific mortality in adult KTRs who died with a functioning allograft. We also studied 1- and 10-year trends in the various causes of mortality. Of 210,327 KTRs who received their first kidney transplant from 1996 to 2014, 3.2% died within 1 year after transplant. Cardiovascular deaths constituted the majority (24.7%), followed by infectious (15.2%) and malignant (2.9%) causes; 40.1% of deaths had no reported cause. Using 1996 as the referent year, all-cause as well as cardiovascular mortality declined, whereas mortality due to malignancy did not. For analyses of 10-year mortality, we studied 94,384 patients who received a first kidney transplant from 1996 to 2005. Of those, 22.1% died over 10 years and the causative patterns of their causes of death were similar to those associated with 1-year mortality. Despite the downtrend in mortality over the last 2 decades, a significant percentage of KTRs die in 10-years with a functioning graft, and cardiovascular mortality remains the leading cause of death. These data also highlight the need for diligent collection of mortality data in KTRs.


Validity and Reliability of the Banff Patellofemoral Instability Instrument 2.0 in an Adolescent Population.
Lateral patellofemoral instability is a relatively common problem in the adolescent population. Subjective and objective patient outcomes are commonly used to evaluate treatment success or failure. The Banff Patellofemoral Instability Instrument (BPII) and Paediatric International Knee Documentation Committee (Pedi-IKDC) Subjective Knee Form are patient-reported outcome measures that have been used with an adolescent population previously. The BPII 2.0 is a shortened version of the BPII and has not been validated in an adolescent population. The purpose of the current study was to validate the BPII 2.0 with an adolescent population. This was a multicenter study where patients were recruited from 3 tertiary orthopaedic surgery clinics. A convenience sample (n=140 adolescent patients) with a confirmed diagnosis of lateral patellofemoral instability and who had failed conservative treatment was referred to one of the 3 orthopaedic surgeons. All patients completed the BPII 2.0 and Pedi-IKDC before their clinic appointment. Cronbach's alpha and floor/ceiling effects were used to determine the content validity of both instruments. Patients were also interviewed to ask questions about the BPII 2.0 comprehension and importance of items. One clinic site sent out the BPII 2.0 to 30 additional patients twice in 2 weeks to measure the test-retest reliability (intraclass correlation coefficient 2,k). A Pearson r correlation coefficient was used to determine the relationship between the BPII 2.0 and the Pedi-IKDC and criterion validity. Cronbach's alpha values were 0.95 and 0.76 for the BPII 2.0 and Pedi-IKDC, respectively. There was no evidence of floor or ceiling effects for either the BPII 2.0 or the Pedi-IKDC. The Pearson r correlation coefficient between the BPII 2.0 and IKDC baseline scores taken at the initial consultation was 0.65 (P<0.001; 95% confidence interval, 0.94-0.97). The intraclass correlation coefficient (2,k) for the test-retest subsample (n=30) was 0.94. Patient interviews revealed that they thought the BPII 2.0 questions were both important and comprehensible. The BPII 2.0 is a valid, reliable, and disease-specific patient-reported outcome measure that can be used with an adolescent population with lateral patellofemoral instability. The BPII 2.0 has demonstrated criterion validity through its moderately strong correlation to the Pedi-IKDC for adolescents.


Persistent anterograde amnesia due to the artery of Percheron occlusion: a case report.
Bilateral thalamic infarction involving the artery of Percheron (AOP) can cause diagnostic difficulties due to the varying clinical presentations. AOP infarcts presented with isolated memory impairment are not common and the factors affecting the persistence of memory disorders are still unknown. A 41-year-old male patient was hospitalized with acute unconsciousness. MRI disclosed bilateral paramedian thalamic infarction The patient had isolated memory deficit and his anterograde amnesia continued without any change in the past decade. More cases might answer the questions concerning the intra- and extra-thalamic structures responsible for the amnesic syndrome and the factors affecting the persistence of the symptoms.


Psychological interventions for depression in adolescent and adult congenital heart disease.
Adult and adolescent congenital heart disease is increasing in prevalence as better medical care means more children are surviving to adulthood. People with chromic disease often also experience depression. There are several non-pharmacological treatments that might be effective in treating depression and improving quality of life for adults and young adults with congenital heart disease. The aim of this review was to assess the effects of treatments such as psychotherapy, cognitive behavioural therapies and talking therapies for treating depression in this population. To assess the effects (both harms and benefits) of psychological interventions for treating depression in young adults and adults with congenital heart disease. We searched the Cochrane Controlled Trials Register (CCTR) (on The Cochrane Library issue 4, 2002), MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), PsycLIT (1887 to August 2002), the Database of Abstracts of Reviews of Effectiveness (DARE) (Issue 4, 2002 of the Cochrane Library), Biological Abstracts (January 1980 to August 2002), and CINAHL (January 1980 to August 2002). Abstracts from national and international cardiology and psychology conferences and dissertation abstracts were also searched. Randomised controlled trials comparing psychological interventions with no intervention for people over 15 years with depression who have congenital heart disease. Two reviewers independently screened titles and abstracts of studies that were potentially relevant to the review. Studies that were clearly ineligible were rejected. Two reviewers independently assessed the abstracts or full papers for inclusion criteria. Further information was sought from the authors where papers contained insufficient information to make a decision about eligibility. No randomised controlled trials were identified. Depression is common in patients with congenital heart disease and can exacerbate the physical consequences of the illness. There are effective pharmacological and non-pharmacological treatments for depression, but we have not been able to identify any trials showing the effectiveness of non-pharmacological treatments. A well designed randomised controlled trial is needed to assess the effects of psychological interventions for depression in congenital heart disease.


Quantification of ultraviolet (UV) radiation in the shade and in direct sunlight.
Ultraviolet (UV) radiation is associated with negative health effects, including sun damage and skin cancer. The purpose of this study is to compare the protective effects of the shade provided by a sun umbrella versus that provided by a tree. Sun sensors that register the level and dose of UV radiation were placed in the shade and in direct sunlight. Measurements were recorded every half hour between the hours of 12:30 p.m. and 3:00 p.m. in Sacramento, California. The results suggest that the level of UV radiation in the shade is not zero. The sensors located in tree shade indicated that over 5% of UV radiation was detected in the shade. The sensors located in sun-umbrella shade showed that greater than 17% of UV radiation reached the shade. The sun sensors used in our study collected UV radiation data relevant to UV index; however, they did not differentiate between UVA, UVB, visible, and infrared light. The amount of UV radiation detected in the shade is not zero, thus regular sunscreen use and other sun protective practices should be followed to reduce the risk of sun damage and skin cancer.


The DnaJ domain of polyomavirus large T antigen is required to regulate Rb family tumor suppressor function.
Tumor suppressors of the retinoblastoma susceptibility gene family regulate cell growth and differentiation. Polyomavirus large T antigens (large T) bind Rb family members and block their function. Mutations of large T sequences conserved with the DnaJ family affect large T binding to a cellular DnaK, heat shock protein 70. The same mutations abolish large T activation of E2F-containing promoters and Rb binding-dependent large T activation of cell cycle progression. Cotransfection of a cellular DnaJ domain blocks wild-type large T action, showing that the connection between the chaperone system and tumor suppressors is direct. Although they are inactive in assays dependent on Rb family binding, mutants in the J region retain the ability to associate with pRb, p107, and p130. This suggests that binding of Rb family members by large T is not sufficient for their inactivation and that a functional J domain is required as well. This work connects the DnaJ and DnaK molecular chaperones to regulation of tumor suppressors by polyomavirus large T.


A Case of Gastric Cancer with Neuroendocrine Carcinoma, Signet Ring Cell Carcinoma Components, and Intramural Metastases.
Many neuroendocrine carcinomas exhibit medullary infiltration and expanded proliferation. Differentiated tubular adenocarcinoma is frequently seen in the superficial region in many neuroendocrine carcinoma cases. However, the present case showed non-medullary infiltration and signet ring cell carcinoma in the superficial region, with intramural metastases distributed throughout the whole of the stomach. A 67-year-old man was referred to our institution for treatment of gastric cancer. Type IIc-like advanced gastric cancer was detected in the greater curvature of the middle body of the stomach. The patient underwent total gastrectomy, splenectomy with D2 lymph node dissection, and Roux-en-Y reconstruction with curative resection. The tumor was diagnosed as a large-cell endocrine carcinoma of the stomach. A solid growth of signet ring cells was seen in the mucosa and submucosa. Intramural metastases were observed in many other depressed lesions. Large-cell carcinoma invaded the submucosa, mainly in the intramural metastatic site. Metastasis to one lesser curvature lymph node was also seen on histological examination. The final diagnosis was a gastric cancer of type 0-IIc (T4a) [M] (with intramural metastases) at T4aN1H0P0M0 Stage IIIA. This patient has remained alive without recurrence for 72 months after surgery. We recommend close preoperative examination of neuroendocrine carcinoma, taking intramural metastases into consideration.


Nitric oxide is a key molecule serving as a bridge between radiation-induced bystander and adaptive responses.
A classical paradigm of radiation biology asserts "targeted effect" that all radiation effects on cells, tissues and organisms are due to the direct action of radiation. However, over the past two decades, a paradigm of radiation biology has undergone a shift away from "targeted effect" relationships and towards complex ongoing "intra- and inter-cellular responses", which involve not only targeted but also non-targeted ones. These responses include now familiar, but still fully unknown, phenomena associated with low-dose/low-dose-rate radiation exposure such as adaptive responses, bystander responses, low-dose hypersensitivity, and genomic instability. The mechanisms underlying these responses often involve biochemical/molecular signals that respond to targeted and non-targeted events. Matsumoto et al. have previously found that nitric oxide functions as initiators of radiation-induced bystander and adaptive responses. These findings suggest correlations between the radioadaptive and bystander responses. The present review focuses on these two phenomena by summarizing observations supporting their existence, and discussing the linkage between them from the aspect of production of reactive nitrogen species.


ZO-1 Intracellular Localization Organizes Immune Response in Non-Small Cell Lung Cancer.
Delocalization of zonula occludens-1 (ZO-1) from tight junctions plays a substantial role in epithelial cell plasticity observed during tumor progression. In vitro, we reported an impact of ZO-1 cyto-nuclear content in modulating the secretion of several pro-inflammatory chemokines. In vivo, we demonstrated that it promotes the recruitment of immune cells in mouse ear sponge assays. Examining lung cancers, we showed that a high density of CD8 cytotoxic T cells and Foxp3 immunosuppressive regulatory T cells in the tumor microenvironment correlated with a cyto-nuclear expression of ZO-1. Taken together, our results support that, by affecting tumor cell secretome, the cyto-nuclear ZO-1 pool may recruit immune cells, which could be permissive for tumor progression.


Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency.
Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. RADAR and conventional geometries were compared further in a rat bilateral carotid artery-internal jugular vein fistula model. There was decreased cell proliferation and neointimal hyperplasia in the A-V configuration in male and female animals, but no difference in hypoxia between the A-V and V-A configurations. Similar trends were seen in uremic male rats. The A-V configuration also associated with increased peak systolic velocity and expression of Kruppel-like factor 2 and phosphorylated endothelial nitric oxide synthase, consistent with improved hemodynamics. Computed tomography and ultrasound-informed computational modeling showed different hemodynamics in the A-V and V-A configurations, and improving the hemodynamics in the V-A configuration was protective against neointimal hyperplasia. These findings collectively demonstrate that RADAR is a durable surgical option for patients requiring radial-cephalic AVF for hemodialysis access.


Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects.
In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (<1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding affinities are rationalised with the help of the three-dimensional structures and quantum-mechanical calculations. Three effects seem to be involved: Firstly, the binding pocket is too small for the largest ligands with ethyl and methyl. Secondly, for the other ligands, the affinity seems to be determined mainly by desolvation effects, disfavouring the polar substituents, but this is partly counteracted by the cation-π interaction with Arg144, which stacks on top of the substituted tetrafluorophenyl group in all complexes. The results provide detailed insight into interactions of fluorinated phenyl moieties with arginine-containing protein binding sites and the complex interplay of different energetic components in defining the binding affinity.


Disease control outcomes of stereotactic body radiation therapy or moderate hypo-fractionation for prostate cancer: Real-world experience at two Canadian centers.
Advantages of using stereotactic body radiation therapy to treat prostate cancer include short treatment times, decreased costs, and limited toxicity. Randomized trial outcomes comparing 5-fraction stereotactic body radiation therapy to conventionally fractionated radiotherapy or hypo-fractionated radiation therapy are pending. We report the 10-year experience with 5-fraction stereotactic body radiation therapy and hypo-fractionated radiation therapy at two Canadian centers. Patients with low- or intermediate-risk prostate cancer treated with stereotactic body radiation therapy alone (35-40 Gy in 5 fractions) or hypo-fractionated radiation therapy alone (60-62 Gy in 20 fractions) in the period of July 2010 and June 2020. The biochemical relapse-free survival, PSA nadir, interval time to PSA nadir, time to biochemical recurrence (2 ng/ml above PSA nadir) and overall survival were reviewed. Outcomes between treatment groups were compared after propensity-matching by patient baseline characteristics. Kaplan-Meier curves were used to assess biochemical relapse-free survival and overall survival. We identified 205 and 513 patients with low or intermediate-risk prostate cancer who were treated with stereotactic body radiation therapy or hypo-fractionation, respectively. Intermediate-risk category composed 81% and 95% of the stereotactic body radiation therapy and hypo-fractionated radiation therapy cohorts, respectively. After a median follow up of 58.6 months for the stereotactic body radiation therapy cohort and 45.0 months for the hypo-fractionated cohort, biochemical relapse-free survival and overall survival were not significantly different between treatment groups. The 5-year biochemical relapse-free survival rates were 92.1% and 93.6% and overall survival rates were 96.4% and 95.0% for the stereotactic body radiation therapy and hypo-fractionated cohorts, respectively, after propensity-matching. Stereotactic body radiation therapy resulted in a significantly lower PSA nadir (0.18 ng/ml) compared to hypo-fractionated radiation therapy (0.48 ng/ml) in patients with low-risk prostate cancer. Mean time to biochemical recurrence was not different between treatment groups. Stereotactic body radiation therapy is an effective treatment option for low and intermediate-risk prostate cancer with encouraging biochemical relapse-free survival and overall survival rates comparable with hypo-fractionated radiation therapy.


The Evergreen gene is essential for flower initiation in carnation.
One of the leading cut-flower crops in the world, the greenhouse carnation (Dianthus caryophyllus), has been subjected to intense breeding efforts for the past few hundred years. As an ornamental crop, flowering and flower architecture are major breeding targets that are constantly in demand. In an ongoing breeding program aimed at improving these characteristics, two mutants heterozygous for a mutation in a gene termed evergreen (e) were identified. In these mutants, spike-like clusters of bracteoles subtend each flower. Genetic analysis of the mutants confirmed the semidominant nature of this nuclear mutation and that the two original mutants were allelic at the evergreen locus. In homozygous mutant plants, a more severe phenotype was observed. Flower formation was completely blocked and spikelike clusters of bracteoles did not subtend any flowers. Morphological characterization of mutant plants revealed that vegetative growth and inflorescence structure are not affected by the mutant allele. In plants heterozygous for the evergreen mutation, fertility, petal and pistil length, calyx diameter, and stamen number were not affected. However, flowers from these heterozygous plants had a reduced number of petals, suggesting an intriguing link between evergreen and the double flower (d) gene that determines petal number in carnation. The control by evergreen of bracteole formation, floral meristem initiation, and petal number in carnation is discussed in comparison to the recessive leafy (lfy) and floricaula (flo) mutants of Arabidopsis and Antirrhinum, respectively.


Gender imbalances in the editorial activities of a selective journal run by academic editors.
The fairness of decisions made at various stages of the publication process is an important topic in meta-research. Here, based on an analysis of data on the gender of authors, editors and reviewers for 23,876 initial submissions and 7,192 full submissions to the journal eLife, we report on five stages of the publication process. We find that the board of reviewing editors (BRE) is men-dominant (69%) and that authors disproportionately suggest male editors when making an initial submission. We do not find evidence for gender bias when Senior Editors consult Reviewing Editors about initial submissions, but women Reviewing Editors are less engaged in discussions about these submissions than expected by their proportion. We find evidence of gender homophily when Senior Editors assign full submissions to Reviewing Editors (i.e., men are more likely to assign full submissions to other men (77% compared to the base assignment rate to men RE of 70%), and likewise for women (41% compared to women RE base assignment rate of 30%))). This tendency was stronger in more gender-balanced scientific disciplines. However, we do not find evidence for gender bias when authors appeal decisions made by editors to reject submissions. Together, our findings confirm that gender disparities exist along the editorial process and suggest that merely increasing the proportion of women might not be sufficient to eliminate this bias. Measures accounting for women's circumstances and needs (e.g., delaying discussions until all RE are engaged) and raising editorial awareness to women's needs may be essential to increasing gender equity and enhancing academic publication.


Polymorphisms of F2 (G20210A), F5 (G1691A), F 7 (G10976A), F 13(G13T), FGB, ITGA2, ITGB3, PAI-I genes and its association with thrombotic complications in patients suffering from Takayasu aortoarteritis of Urals population.
Cardiovascular complications, especially thrombotic events, are characteristic for Takayasu arteritis (TA). These events significantly deteriorate the patients' quality of life and cause disability and preterm death. Coagulation factor II (F2, G20210A), coagulation factor V (F5, G1691A, Leiden), coagulation factor VII (F7, G10976A), coagulation factor XIII (F13, G13T), fibrinogen (FGB), platelet alpha subunit of transmembrane receptor for collagens and related proteins (ITGA2), platelet glycoprotein (ITGB3), and plasminogen activator inhibitor-1 (PAI-I) gene polymorphisms coexist with TA, and their pathophysiologic interaction needs to be studied. A total of 43 patients with TA were examined for nucleotides polymorphism in F2 (G20210A), F5 (G1691A, Leiden), F7 (G10976A), F13 (G13T), FGB, ITGA2, ITGB3, and PAI-I genes using polymerase chain reaction. Moreover, 130 sex- and age-adjusted healthy controls without a history of any thrombotic complications were enrolled. Among the patients with TA, there were 34 women aged between 17 and 77 (mean 49, median 49; Q1-Q3, 36-61) years and 9 men aged between 20 and 66 (mean 37.8, median 38; Q1-Q3: 31-45) years. Thrombotic complications were recorded in 22 (51%) patients with TA. Comparison of thrombophilia markers genotypes in patients with TA and healthy controls revealed homozygous and heterozygous mutation in ITGA2 (p<0.0001) and PAI-I genes (p=0.026). The frequency of occurrence of hereditary thrombophilia markers in patients with TA was assessed. Detection of the PAI-I gene mutation was significantly more frequent (p=0.032) in patients with TA with a history of thrombotic events than in those with no thrombosis history. Detection of multiple (more than 4 genes) simultaneous mutations of thrombophilia markers was significantly (p=0.0001) more frequent in patients with TA with a history of thrombotic events. Assessment of hereditary thrombophilia genetic markers reveals additional (genetic) risk markers of thrombotic complications in patients with TA and may help in decision making for antiplatelet and/or anticoagulant treatment in patients with TA to reduce the risk of thrombotic complications.


Sodium-dependent amino acid transport is preserved in lyophilized reconstituted apical membranes from intestinal epithelium.
We demonstrate for the first time that functional electrogenic Na(+)-dependent amino acid transport is preserved for extended periods when purified brush border membranes prepared in hypotonic media are lyophilized and then rehydrated in buffer containing mannitol, NaSCN, and/or KSCN/valinomycin. Reconstituted lyophilized apical membranes from small intestine formed morphologically, physiologically, and thermodynamically normal vesicles which transported L-alanine via system B into an osmotically active space energized by secondary active transport, as measured under equilibrium and nonequilibrium conditions. The lyophilized membranes are readily prepared and stored, thereby providing a means to pool large quantities of formed vesicles that are useful in examining cloned and reconstituted native amino acid transporter polypeptides.


[Methods of evaluating the efficacy of combinations of aminoglycosides with penicillins and their value for the possibility of predicting the therapeutic effect in patients].
The efficacy of the combinations of aminoglycosides and penicillin with respect to Pseudomonas, Klebsiella and Escherichia strains was estimated with the methods of two-fold serial dilutions of aminoglycosides and constant concentrations of penicillin and the "chess board" method. Correlation between the synergistic effect and sensitivity of the strains to separate components of the combinations was observed. For prediction of the combination efficacy these methods are not useful, since they are labour-intensive and their results are very variable. In this connection a simple informative test is recommended. With the use of this test it is possible to judge the chemotherapeutic efficacy of antibiotics and their combinations by the value of the serum antibacterial activity (titer) against the infection causative agent. The blood serum titer of at least 1:8 is accompanied by a pronounced effect. The test also indirectly provides information on the sensitivity of isolated pathogens and adequacy of the drug blood levels after administration of the chosen dose.


Functional mapping for quantitative trait loci governing growth rates: a parametric model.
Are there-specific quantitative trait loci (QTL) governing growth rates in biology? This is emerging as an exciting but challenging question for contemporary developmental biology, evolutionary biology, and plant and animal breeding. In this article, we present a new statistical model for mapping QTL underlying age-specific growth rates. This model is based on the mechanistic relationship between growth rates and ages established by a variety of mathematical functions. A maximum likelihood approach, implemented with the EM algorithm, is developed to provide the estimates of QTL position, growth parameters characterized by QTL effects, and residual variances and covariances. Based on our model, a number of biologically important hypotheses can be formulated concerning the genetic basis of growth. We use forest trees as an example to demonstrate the power of our model, in which a QTL for stem growth diameter growth rates is successfully mapped to a linkage group constructed from polymorphic markers. The implications of the new model are discussed.


Positron emission tomography visualized stimulation of the vestibular organ is localized in Heschl's gyrus.
The existence of a human primary vestibular cortex is still debated. Current knowledge mainly derives from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) acquisitions during artificial vestibular stimulation. This may be problematic as artificial vestibular stimulation entails coactivation of other sensory receptors. The use of fMRI is challenging as the strong magnetic field and loud noise during MRI may both stimulate the vestibular organ. This study aimed to characterize the cortical activity during natural stimulation of the human vestibular organ. Two fluorodeoxyglucose (FDG)-PET scans were obtained after natural vestibular stimulation in a self-propelled chair. Two types of stimuli were applied: (a) rotation (horizontal semicircular canal) and (b) linear sideways movement (utriculus). A comparable baseline FDG-PET scan was obtained after sitting motion-less in the chair. In both stimulation paradigms, significantly increased FDG uptake was measured bilaterally in the medial part of Heschl's gyrus, with some overlap into the posterior insula. This is the first neuroimaging study to visualize cortical processing of natural vestibular stimuli. FDG uptake was demonstrated in the medial-most part of Heschl's gyrus, normally associated with the primary auditory cortex. This anatomical localization seems plausible, considering that the labyrinth contains both the vestibular organ and the cochlea.


Status of cervical cancer screening among adolescents and young adults (AYA) in Japan.
Cervical cancer ranks high among the cancers that affect people in their 20s and 30s. Cervical cancer is characterized by the presence of precancerous lesions, which can be detected by cancer screenings; some precancerous lesions are amenable to treatment, which can halt the progression to invasive cancer. As a result, cervical cancer screening has been shown to reduce the incidence of invasive cancer and its mortality. On the other hand, many precancerous lesions do not progress to invasive cancer, but stagnate or disappear spontaneously. In Japan, there is a nationwide cytological screening program for residents, and the screening is performed every two years after the age of 20. There are also screening programs provided by the workplaces in Japan. According to the National Health Survey 2019, the checkup rates of any type of cervical cancer screenings are low: 15.1% for those aged 20-24, 36.6% for those aged 25-29, and 49.4% for those aged 30-34. Statistics are reported every year for the nationwide screening, and according to them, the positive screening rate is 2.1% for all ages, but 4.5% and 3.2% for those in their 20s and 30s, respectively. On the other hand, the percentage of people with positive test results who undergo follow-up examinations or confirmatory tests should be at least 90%, but it is 72.1% for all ages, 72.0% for those in their 30s, and even lower for those in their 20s, at 67.1%. Improving the rate of people getting screenings and subsequent examinations is a challenge even among the young.


Is halofantrine still advisable in malaria attacks?
Halofantrine is an antimalarial drug which is widely prescribed for the treatment of infections with chloroquine-resistant strains of Plasmodium falciparum. Chemically, it is a phenanthrene methanol, belonging to the aryl-amino-alcohol family. It has recently been recognized that this drug may induce rare but serious, cardiotoxic effects, including lengthening of the QTc interval, 'torsade de pointes' and induction of late ventricular potentials. These events are thought to be related to a quinidine-like action of the drug. In addition, severe haemolytic accidents have been reported, mimicking blackwater fever and indicating an immunological process. As a result of these side-effects, new guidelines for prescription and more cautious use of halofantrine, particularly as a stand-by treatment for febrile access among travellers, are required.