Data management in substance use disorder treatment research: Implications from data harmonization of National Institute on Drug Abuse-funded randomized controlled trials.
Secondary analysis of data from completed randomized controlled trials is a critical and efficient way to maximize the potential benefits from past research. De-identified primary data from completed randomized controlled trials have been increasingly available in recent years; however, the lack of standardized data products is a major barrier to further use of these valuable data. Pre-statistical harmonization of data structure, variables, and codebooks across randomized controlled trials would facilitate secondary data analysis, including meta-analyses and comparative effectiveness studies. We describe a pre-statistical data harmonization initiative to standardize de-identified primary data from substance use disorder treatment randomized controlled trials funded by the National Institute on Drug Abuse available on the National Institute on Drug Abuse Data Share website. Standardized datasets and codebooks with consistent data structures, variable names, labels, and definitions were developed for 36 completed randomized controlled trials. Common data domains were identified to bundle data files from individual randomized controlled trials according to relevant concepts. Variables were harmonized if at least two randomized controlled trials used the same instruments. The structures of the harmonized data were determined based on the feedback from clinical trialists and substance use disorder research experts. We have created a harmonized database of variables across 36 randomized controlled trials with a build-in label and a brief definition for each variable. Data files from the randomized controlled trials have been consistently categorized into eight domains (enrollment, demographics, adherence, adverse events, physical health measures, mental-behavioral-cognitive health measures, self-reported substance use measures, and biologic substance use measures). Standardized codebooks and concordance tables have also been developed to help identify instruments and variables of interest more easily. The harmonized data of randomized controlled trials of substance use disorder treatments can potentially promote future secondary data analysis of completed randomized controlled trials, allowing combining data from multiple randomized controlled trials and provide guidance for future randomized controlled trials in substance use disorder treatment research.


Low-intensity ultrasound induced cavitation and streaming in oxygen-supersaturated water: Role of cavitation bubbles as physical cleaning agents.
A number of acoustic and fluid-dynamic phenomena appear in ultrasonic cleaning baths and contribute to physical cleaning of immersed surfaces. Propagation and repeated reflection of ultrasound within cleaning baths build standing-wave-like acoustic fields; when an ultrasound intensity gradient appears in the acoustic fields, it can in principle induce steady streaming flow. When the ultrasound intensity is sufficiently large, cavitation occurs and oscillating cavitation bubbles are either trapped in the acoustic fields or advected in the flow. These phenomena are believed to produce mechanical action to remove contaminant particles attached at material surfaces. Recent studies suggest that the mechanical action of cavitation bubbles is the dominant factor of particle removal in ultrasonic cleaning, but the bubble collapse resulting from high-intensity ultrasound may be violent enough to give rise to surface erosion. In this paper, we aim to carefully examine the role of cavitation bubbles from ultrasonic cleaning tests with varying dissolved gas concentration in water. In our cleaning tests using 28-kHz ultrasound, oxygen-supersaturated water is produced by oxygen-microbubble aeration and used as a cleaning solution, and glass slides spin-coated with silica particles of micron/submicron sizes are used to define cleaning efficiency. High-speed camera recordings and Particle Image Velocimetry analysis with a pressure oscillation amplitude of 1.4 atm at the pressure antinode show that the population of cavitation bubbles increases and streaming flow inside the bath is promoted, as the dissolved oxygen supersaturation increases. The particle removal is found to be achieved mainly by the action of cavitation bubbles, but there exists optimal gas supersaturation to maximize the removal efficiency. Our finding suggests that low-intensity ultrasound irradiation under the optimal gas supersaturation in cleaning solutions allows for having mild bubble dynamics without violent collapse and thus cleaning surfaces without cavitation erosion. Finally, observations of individual bubble dynamics and the resulting particle removal are reported to further support the role of cavitation bubbles as cleaning agents.


Neuropeptide substance P improves osteoblastic and angiogenic differentiation capacity of bone marrow stem cells in vitro.
Our previous work showed that implanting a sensory nerve or vascular bundle when constructing vascularized and neurotized bone could promote bone osteogenesis in tissue engineering. This phenomenon could be explained by the regulatory function of neuropeptides. Neuropeptide substance P (SP) has been demonstrated to contribute to bone growth by stimulating the proliferation and differentiation of bone marrow stem cells (BMSCs). However, there have been no prior studies on the association between Wnt signaling and the mechanism of SP in the context of BMSC differentiation. Our results have shown that SP could enhance the differentiation of BMSCs by activating gene and protein expression via the Wnt pathway and by translocating β-catenin, which can be inhibited by Wnt signaling blocker treatment or by the NK-1 antagonist. SP could also increase the growth factor level of bone morphogenetic protein-2 (BMP-2). Additionally, SP could enhance the migration ability of BMSCs, and the promotion of vascular endothelial growth factor (VEGF) expression by SP has been studied. In conclusion, SP could induce osteoblastic differentiation via the Wnt pathway and promote the angiogenic ability of BMSCs. These results indicate that a vascularized and neurotized tissue-engineered construct could be feasible for use in bone tissue engineering strategies.


An efficient system to establish biopsy-derived trophoblastic cell lines from bovine embryos.
Trophoblastic cells play a crucial role in implantation and placentogenesis and can be used as a model to provide substantial information on the peri-implantation period. Unfortunately, there are few cell lines for this purpose in cattle because of the difficulty of raising successive cell stocks in the long-term. Our results show that the combination of a monolayer culture system in microdrops on a surface treated with gelatin and the employment of conditioned media from mouse embryonic fibroblasts support the growth of bovine trophoblastic cells lines from an embryo biopsy. Expression profiles of mononucleate- and binucleate-specific genes in established trophoblastic cells lines represented various stages of gestation. Moreover, the ability to expand trophoblastic cell lines for more than 2 yr together with pluripotency-related gene expression patterns revealed certain self-renewal capacity. In summary, we have developed a system to expand in vitro trophoblastic cells from an embryo biopsy that solves the limitations of using amplified DNA from a small number of cells for bovine embryo genotyping and epigenotyping and, on the other hand, facilitates the establishment of trophoblastic cell lines that can be useful as peri-implantation in vitro models.


Research on the stability of a rabbit dry eye model induced by topical application of the preservative benzalkonium chloride.
Dry eye is a common disease worldwide, and animal models are critical for the study of it. At present, there is no research about the stability of the extant animal models, which may have negative implications for previous dry eye studies. In this study, we observed the stability of a rabbit dry eye model induced by the topical benzalkonium chloride (BAC) and determined the valid time of this model. Eighty white rabbits were randomly divided into four groups. One eye from each rabbit was randomly chosen to receive topical 0.1% BAC twice daily for 2 weeks (Group BAC-W2), 3 weeks (Group BAC-W3), 4 weeks (Group BAC-W4), or 5 weeks (Group BAC-W5). Fluorescein staining, Schirmer's tests, and conjunctival impression cytology were performed before BAC treatment (normal) and on days 0, 7, 14 and 21 after BAC removal. The eyeballs were collected at these time points for immunofluorescence staining, hematoxylin and eosin (HE) staining, and electron microscopy. After removing BAC, the signs of dry eye in Group BAC-W2 lasted one week. Compared with normal, there were still significant differences in the results of Schirmer's tests and fluorescein staining in Groups BAC-W3 and BAC-W4 on day 7 (P<0.05) and in Group BAC-W5 on day 14 (P<0.05). Decreases in goblet cell density remained stable in the three experimental groups at all time points (P<0.001). Decreased levels of mucin-5 subtype AC (MUC5AC), along with histopathological and ultrastructural disorders of the cornea and conjunctiva could be observed in Group BAC-W4 and particularly in Group BAC-W5 until day 21. A stable rabbit dry eye model was induced by topical 0.1% BAC for 5 weeks, and after BAC removal, the signs of dry eye were sustained for 2 weeks (for the mixed type of dry eye) or for at least 3 weeks (for mucin-deficient dry eye).


Black milk--an essay on the nature and importance of saying.
Three types of verbal communication are considered: saying, speaking and talking. While speaking covers a topic and talking fills a social void, saying is defined here as a communication to a particular person at a certain moment with a specific intended meaning or effect. Examples of saying are presented from the Bible and the author's interactions in cases of dementia and catatonia, and a poem by Celan. Examples are brought to help define the role of the psychotherapist in communicating with the depressive world view of his/her patients.


The autoinflammation-associated NLRC4V341A mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice.
Autoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood. Here, we developed and characterized a novel genetic mouse model expressing a murine version of the AIFEC-associated NLRC4V341A mutation from its endogenous Nlrc4 genomic locus. NLRC4V341A expression in mice recapitulated increased circulating IL-18 levels as observed in AIFEC patients. Housing NLRC4V341A-expressing mice in germfree (GF) conditions showed that these systemic IL-18 levels were independent of the microbiota, and unmasked an additional IL-18-inducing effect of NLRC4V341A expression in the intestines. Remarkably, elevated IL-18 levels did not provoke detectable intestinal pathologies in NLRC4V341A-expressing mice, even not upon genetically ablating IL-18 binding protein (IL-18BP), which is an endogenous IL-18 inhibitor that has been used therapeutically in AIFEC. In addition, NLRC4V341A expression did not alter susceptibility to the NLRC4-activating gastrointestinal pathogens Salmonella Typhimurium and Citrobacter rodentium. As observed in AIFEC patients, mice expressing a murine NLRC4V341A mutant show elevated systemic IL-18 levels, suggesting that the molecular mechanisms by which this NLRC4V341A mutant induces excessive IL-18 production are conserved between humans and mice. However, while our GF and infection experiments argue against a role for commensal or pathogenic bacteria, identifying the triggers and mechanisms that synergize with IL-18 to drive NLRC4V341A-associated pathologies will require further research in this NLRC4V341A mouse model.


Analysis of colonization factor antigen I, an adhesin of enterotoxigenic Escherichia coli O78:H11: fimbrial morphology and location of the receptor-binding site.
Colonization factor antigen I (CFA/I) of enterotoxigenic Escherichia coli was dissociated into one type of subunit (15 kDa). The dissociation was achieved either by heating CFA/I in sodium dodecyl sulfate at 100 degrees C or by heating it for 20 min in water. Heating in water to 100 degrees C yielded only in the 15-kDa subunit, but heating to 85 degree C yielded small amounts of oligomers in addition. The monomeric subunits obtained after heating in water are stable, as demonstrated by gel permeation chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis without heating prior to the electrophoretic run. These subunits inhibited CFA/I-induced hemagglutination, indicating that they had maintained their receptor-binding properties. When the hybridoma technique was used, two types of monoclonal anti-CFA/I antibodies were obtained. Antibodies obtained by immunization with the purified subunits were more reactive with subunits than with fimbriae, as shown by enzyme-linked immunosorbent assay. These antibodies strongly inhibited CFA/I-induced hemagglutination. When examined by immunoelectron microscopy, these antibodies seemed to label the fimbrial tips. A similar labeling pattern was obtained with gold particles modified with the receptor ganglioside GM2. Antibodies obtained by immunization with fimbriae reacted in enzyme-linked immunosorbent assays equally well with fimbriae and subunits. They inhibited CFA/I-induced hemagglutination only slightly. Immunoelectron microscopy revealed that these antibodies labeled the fimbriae densely and regularly over their entire lengths. In a coagglutination experiment with Staphylococcus aureus and monoclonal antibodies, the subunits retained their receptor-binding properties. From these results, we conclude that CFA/I fimbriae consist entirely of one type of adhesive subunit, of which only the one at the tip is accessible to the receptor.


Imaging phosphatidylinositol 4-phosphate dynamics in living plant cells.
Polyphosphoinositides represent a minor group of phospholipids, accounting for less than 1% of the total. Despite their low abundance, these molecules have been implicated in various signalling and membrane trafficking events. Phosphatidylinositol 4-phosphate (PtdIns4P) is the most abundant polyphosphoinositide. (32)Pi-labelling studies have shown that the turnover of PtdIns4P is rapid, but little is known about where in the cell or plant this occurs. Here, we describe the use of a lipid biosensor that monitors PtdIns4P dynamics in living plant cells. The biosensor consists of a fusion between a fluorescent protein and a lipid-binding domain that specifically binds PtdIns4P, i.e. the pleckstrin homology domain of the human protein phosphatidylinositol-4-phosphate adaptor protein-1 (FAPP1). YFP-PH(FAPP1) was expressed in four plant systems: transiently in cowpea protoplasts, and stably in tobacco BY-2 cells, Medicago truncatula roots and Arabidopsis thaliana seedlings. All systems allowed YFP-PH(FAPP1) expression without detrimental effects. Two distinct fluorescence patterns were observed: labelling of motile punctate structures and the plasma membrane. Co-expression studies with organelle markers revealed strong co-labelling with the Golgi marker STtmd-CFP, but not with the endocytic/pre-vacuolar marker GFP-AtRABF2b. Co-expression with the Ptdins3P biosensor YFP-2 x FYVE revealed totally different localization patterns. During cell division, YFP-PH(FAPP1) showed strong labelling of the cell plate, but PtdIns3P was completely absent from the newly formed cell membrane. In root hairs of M. truncatula and A. thaliana, a clear PtdIns4P gradient was apparent in the plasma membrane, with the highest concentration in the tip. This only occurred in growing root hairs, indicating a role for PtdIns4P in tip growth.


Total hip arthroplasty after failed treatment of proximal femur fracture.
Total hip arthroplasty (THA) is a good option as a salvage procedure after failed treatment of proximal femur fracture. The anatomy of the proximal femur, however, makes this surgery complicated and challenging. The purpose of this study was to evaluate the radiographic and clinical outcomes of THA after failed treatment of proximal femur fractures. We retrospectively analysed 50 consecutive THAs (42 women, 8 men; mean age 77 years) after failed treatment of a proximal femur fracture. Mean postoperative follow-up was 58.1 months. Preoperative diagnoses were femoral neck fracture in 18 hips and trochanteric fracture in 32 hips, including three that were infected. Failure resulted from cutout in 22 cases, osteonecrosis in 12, non-union with failed fixation in nine, postoperative osteoarthritis in four, and infection in three. Factors compared included radiographic assessment, complication rate, visual analogue scale (VAS), and Harris Hip Scores (HHS). Radiographic variables included femoral neck anteversion and cup and stem alignment. Absolute values of the differences in femoral neck anteversion between the affected and healthy sides were 6.0° in the femoral neck fracture group and 19.2° in the trochanteric fracture group (p = 0.01). There were no significant differences in cup anteversion (p = 0.20) or stem anteversion (p = 0.08). The complication rate was significantly higher in the trochanteric fracture group than in the femoral neck fracture group (25 vs 0%, p < 0.0001). Postoperative complications in the trochanteric fracture group included three periprosthetic fractures (9.4%), two dislocations (6.3%), two surgical-site infections (6.3%), and one stem penetration (3.1%). Although no significant differences between groups were seen in the VAS or HHS at final follow-up (p = 0.32, 0.09, respectively), these measures were significantly improved at final follow-up in both groups (p < 0.0001 for both). Performing THA after failed treatment of trochanteric fractures requires consideration of complication risk and incorrect femoral neck anteversion.


Accuracy of optimized branched algorithms to assess activity-specific physical activity energy expenditure.
To assess the activity-specific accuracy achievable by branched algorithm (BA) analysis of simulated daily living physical activity energy expenditure (PAEE) within a sedentary population. Sedentary men (n = 8) and women (n = 8) first performed a treadmill calibration protocol, during which HR, accelerometry (ACC), and PAEE were measured in 1-min epochs. From these data, HR-PAEE and ACC-PAEE regressions were constructed and used in each of six analytic models to predict PAEE from ACC and HR data collected during a subsequent simulated daily living protocol. Criterion PAEE was measured during both protocols via indirect calorimetry. The accuracy achieved by each model was assessed by the root mean square of the difference between model-predicted daily living PAEE and the criterion daily living PAEE (expressed here as percent of mean daily living PAEE). Across the range of activities, an unconstrained post hoc-optimized BA best predicted criterion PAEE. Estimates using individual calibration were generally more accurate than those using group calibration (14% vs 16% error, respectively). These analyses also performed well within each of the six daily living activities, but systematic errors appeared for several of those activities, which may be explained by an inability of the algorithm to simultaneously accommodate a heterogeneous range of activities. Analyses between mean square error by subject and activity suggest that optimization involving minimization of root mean square for total daily living PAEE is associated with decreased error between subjects but increased error between activities. The performance of post hoc-optimized BA may be limited by heterogeneity in the daily living activities being performed.


Community care, competition and coercion: a legal perspective on privatized mental health care.
Even as the Clinton administration considers an increased federal commitment to mental health care, delivery of such care remains fixed at the state level. In Massachusetts, state officials are privatizing mental health care on an unprecedented scale, an experiment that promises to provide better care at lower cost. This Note explores whether privatization can achieve that lofty goal, given a legal system that has made individual patient autonomy its preeminent value. The author concludes that wide-scale privatization and modern notions of self-determination can only coexist with a significant investment in the support services that are critical to the community tenure of former state hospital patients.


The UK-DCD-Risk-Score - practical and new guidance for allocation of a specific organ to a recipient?
Introduction: Multiple factors contribute to the overall outcome in donation after circulatory death liver transplantation. The majority is however inconsistently reported with various acceptance criteria and thresholds, when to decline a specific graft. Recent improvement in outcome was based on an increased awareness of the cumulative risk, combining donor and recipient parameters, which encouraged the community to accept livers with an overall higher risk. Areas covered: This review pictures the large number of risk factors in this field with a special focus on parameters, which contribute to available prediction models. Next, features of the recently developed UK-DCD-Risk-Score, which led to a significantly impaired graft survival, above a suggested threshold of >10 score points, are discussed. The clinical impact of this new model on the background of other prediction tools with their subsequent limitations is highlighted in a next chapter. Finally, we provide suggestions, how to further improve outcomes in this challenging field of transplantation. Expert opinion: Despite the recent development of new prediction models, including the UK-DCD-Risk-Score, which provides a sufficient prediction of graft loss after DCD liver transplantation, the consideration of other confounders is essential to better understand the overall risk and metabolic liver status to improve the comparability of clinical studies. More uniform definitions and thresholds of individual risk factors are required.


[Thoracic endometriosis--the rare pathology in thoracic surgery].
Thoracic hematogenic endometriosis is a rare pathology. A clinical course hasn't pathognomic symptoms, because of it, the diagnosis is established due to histological study. The article presented two cases of female patients, who were suffering from thoracic endometriosis. They were hospitalized to the department of thoracic surgery of Municipal multifield hospital No 2 in Saint-Petersburg. The first patient had a posterior mediastinum tumor with asymptomatic disease course. The second patient was with recurrent catamenial pneumothorax.


Busulfan for allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia: A retrospective study.
Introduction This retrospective study aimed to compare a range of conditioning regimens in children with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Seventh Medical Center of PLA General Hospital between January 2008 and June 2017. Methods Patients were categorized into the Bu (Bu + Flu + Cy + ATG-F regimen) and control (Flu + Cy + ATG-F) groups, with a median follow-up time after HSCT of 3.5 (range, 3.1-6.2) and 3.7 (3.2-5.9) years in the Bu and control groups, respectively. Results No differences were observed between the two groups regarding the median time of peripheral blood neutrophil and platelet engraftment (P = 0.538 and P = 0.491); the 28-day engraftment rates of neutrophils were similar (P = 0.199) although higher for platelets with Bu (P = 0.044). Additionally, graft failure was 0% and 20.0% in the Bu and control groups, respectively (P = 0.004). In both groups, the incidence of grades ⅡI-Ⅳ (or grades Ⅱ-Ⅳ) acute graft-versus-host disease (GVHD) and chronic GVHD was not significantly different (P > 0.05). Moreover, the 3-year overall survival and failure-free survival did not show significant differences (P = 0.670 and P = 0.908). Discussion In children with SAA undergoing allo-HSCT, conditioning regimen with Bu + Flu + Cy + ATG-F is capable of enhancing the myeloablation effect, promoting donor hematopoietic stem cell engraftment, and reducing the graft failure rate. Furthermore, it does not increase the incidence of complications, including GVHD.


Effects of varied lipid core volume and fibrous cap thickness on stress distribution in carotid arterial plaques.
The rupture of atherosclerotic plaques is known to be associated with the stresses that act on or within the arterial wall. The extreme wall tensile stress is usually recognized as a primary trigger for the rupture of the plaque. The present study used one-way fluid-structure interaction simulation to investigate the impacts of fibrous cap thickness and lipid core volume to the wall tensile stress value and distributions on the fibrous cap. Von Mises stress was employed to represent the wall tensile stress (VWTS). A total of 13 carotid bifurcation cases were manipulated based on a base geometry in the study with varied combinations of fibrous cap thickness and lipid core volume in the plaque. Values of maximum VWTS and a stress value of VWTS_90, which represents the cut-off VWTS value of 90% in cumulative histogram of VWTS possessed at the computational nodes on the luminal surface of fibrous cap, were used to assess the risk of plaque rupture for each case. Both parameters are capable of separating the simulation cases into vulnerable and more stable plaque groups, while VWTS_90 is more robust for plaque rupture risk assessment. The results show that the stress level on the fibrous cap is much more sensitive to the changes in the fibrous cap thickness than the lipid core volume. A slight decrease of cap thickness can cause a significant increase of stress. For all simulation cases, high VWTS appears at the fibrous cap near the lipid core (plaque shoulder) regions.


Cone beam computed tomographic measurement of maxillary central incisors to determine prevalence of facial alveolar bone width ≥2 mm.
The initial thickness of maxillary bone has significant impact on the responding level of facial bone and soft tissue after extraction and immediate implant placement. A prevailing notion is that following implant placement in fresh extraction sites, at least 2 mm of facial bone is needed to prevent soft tissue recession, fenestration, and dehiscence. The purpose of this study was to use cone beam computed tomography (CBCT) to measure horizontal width of facial alveolar bone overlying healthy maxillary central incisors and to determine prevalence of bone thickness ≥2 mm. Tomographic data from 101 randomly selected patients were evaluated by two independent observers. Assessments were made of facial bone width at levels 1.0 to 10.0 mm apical to the bone crest. Healthy maxillary central incisors (n= 202) were measured from 101 patient scans. The percent of teeth with facial bone ≥2 mm at levels 1, 2, 3, 4, and 5 mm from the bone crest was 0, 1.5, 2.0, 3.0, and 2.5%, respectively. Overall mean thickness of the bone was 1.05 mm for right and left central incisors combined. The range of individual measurements for all levels was 0 to 5.1 mm. The occurrence of ≥ 2 mm thickness bone measurements increased with increasing depth. However, mean widths observed at levels 6 to 10 mm from the crest ranged only 1.0 to 1.3 mm because of apparent fenestration occurrence (0 mm bone) in approximately 12% of teeth. Overall, no significant differences in bone thickness were found between ethnic, gender, age, or scan groups. Using CBCT, occurrences of ≥2 mm maxillary facial alveolar bone were found on no more than 3% of root surfaces 1.0 to 5.0 mm apical to the bone crest in this sample of maxillary central incisors. The study evidenced prevalence of a thin facial alveolar bone (<2 mm) that may contribute to risk of facial bone fenestration, dehiscence, and soft tissue recession after immediate implant therapy.


A minimal fragment of MUC1 mediates growth of cancer cells.
The MUC1 protein is aberrantly expressed on many solid tumor cancers. In contrast to its apical clustering on healthy epithelial cells, it is uniformly distributed over cancer cells. However, a mechanistic link between aberrant expression and cancer has remained elusive. Herein, we report that a membrane-bound MUC1 cleavage product, that we call MUC1*, is the predominant form of the protein on cultured cancer cells and on cancerous tissues. Further, we demonstrate that transfection of a minimal fragment of MUC1, MUC1*(1110), containing a mere forty-five (45) amino acids of the extracellular domain, is sufficient to confer the oncogenic activities that were previously attributed to the full-length protein. By comparison of molecular weight and function, it appears that MUC1* and MUC1*(1110) are approximately equivalent. Evidence is presented that strongly supports a mechanism whereby dimerization of the extracellular domain of MUC1* activates the MAP kinase signaling cascade and stimulates cell growth. These findings suggest methods to manipulate this growth mechanism for therapeutic interventions in cancer treatments.


Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia: a literature review of pharmaceutical and clinical aspects.
The rate of dermal toxicity has been shown to increase in patients receiving pegylated liposomal doxorubicin (PLD), particularly palmar-plantar erythrodysesthesia (PPE). However, it is difficult to diagnose and treat PLD-related PPE due to its delayed dermal performance, unclear pathogenetic mechanism, and the lack of specific preventive measures. The aim of this study was to provide potential management strategies for PPE associated with PLD. The current article reviews the available data regarding the pharmacological and clinical aspects of PLD, including the formulation and pharmacokinetics of PLD, dose and schedule contribution to PPE, concomitant drugs affecting skin toxicity of PLD, the pathogenesis of PPE, and preventive measures and treatment of PLD-related PPE. The long circulation structure of polyethylene glycol liposomes may be one of the reasons for PPE. PLD has radically different pharmacokinetic characteristics, including prolonged blood circulation time, decreased body distribution volume, and slow clearance. Altering the schedules and doses of PLD or combining it with platinum compounds can optimise clinical efficacy and minimise the occurrence of PPE. Doses of 150-200 mg of pyridoxine daily have been widely used for the prevention and treatment of PPE. Regional cooling and plasma filtration have been used for PPE prophylaxis. To date, the mechanism of PPE induced by PLD remains unclear, and no complete preventive medication has been established. Further research and prospective randomised studies are needed to understand the management options in PLD-related PPE.


Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France.
This study's objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006-2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.


Efficient Acceleration of Reaction Discovery in the Ab Initio Nanoreactor: Phenyl Radical Oxidation Chemistry.
Over the years, many computational strategies have been employed to elucidate reaction networks. One of these methods is accelerated molecular dynamics, which can circumvent the expense required in dynamics to find all reactants and products (local minima) and transition states (first-order saddle points) on a potential energy surface (PES) by using fictitious forces that promote reaction events. The ab initio nanoreactor uses these accelerating forces to study large chemical reaction networks from first-principles quantum mechanics. In the initial nanoreactor studies, this acceleration was done through a piston periodic compression potential, which pushes molecules together to induce entropically unfavorable bimolecular reactions. However, the piston is not effective for discovering intramolecular and dissociative reactions, such as those integral to the decomposition channels of phenyl radical oxidation. In fact, the choice of accelerating forces dictates not only the rate of reaction discovery but also the types of reactions discovered; thus, it is critical to understand the biases and efficacies of these forces. In this study, we examine forces using metadynamics, attractive potentials, and local thermostats for accelerating reaction discovery. For each force, we construct a separate phenyl radical combustion reaction network using solely that force in discovery trajectories. We elucidate the enthalpic and entropic trends of each accelerating force and highlight their efficiency in reaction discovery. Comparing the nanoreactor-constructed reaction networks with literature renditions of the phenyl radical combustion PES shows that a combination of accelerating forces is best suited for reaction discovery.


Evidence that fasting can induce a selective loss of uncoupling protein from brown adipose tissue mitochondria of mice.
The effects of fasting and refeeding on the concentration of uncoupling protein in brown adipose tissue mitochondria have been investigated in mice. Fasting mice for 48 h led to a large decrease in the total cytochrome oxidase activity of the interscapular brown fat pad. Mitochondrial GDP binding and the specific mitochondrial concentration of uncoupling protein also fell on fasting. After 24 h refeeding both GDP binding and the mitochondrial concentration of uncoupling protein were normalized, but there was no alteration in the total tissue cytochrome oxidase activity. Fasting appears to induce a selective loss of uncoupling protein from brown adipose tissue mitochondria, which is rapidly reversible on refeeding.


Multi-Objective Matrix Normalization for Fine-grained Visual Recognition.
Bilinear pooling achieves great success in fine-grained visual recognition (FGVC). Recent methods have shown that the matrix power normalization can stabilize the second-order information in bilinear features, but some problems, e.g., redundant information and over-fitting, remain to be resolved. In this paper, we propose an efficient Multi-Objective Matrix Normalization (MOMN) method that can simultaneously normalize a bilinear representation in terms of square-root, low-rank, and sparsity. These three regularizers can not only stabilize the second-order information, but also compact the bilinear features and promote model generalization. In MOMN, a core challenge is how to jointly optimize three non-smooth regularizers of different convex properties. To this end, MOMN first formulates them into an augmented Lagrange formula with approximated regularizer constraints. Then, auxiliary variables are introduced to relax different constraints, which allow each regularizer to be solved alternately. Finally, several updating strategies based on gradient descent are designed to obtain consistent convergence and efficient implementation. Consequently, MOMN is implemented with only matrix multiplication, which is well-compatible with GPU acceleration, and the normalized bilinear features are stabilized and discriminative. Experiments on five public benchmarks for FGVC demonstrate that the proposed MOMN is superior to existing normalization-based methods in terms of both accuracy and efficiency. The code is available: https://github.com/mboboGO/MOMN.


Comorbid psychiatric disorders in subjects with panic attacks.
Several psychiatric disorders are associated with panic disorder (PD), although the nature of their relationships is unknown. The purpose of this study was to a) document comorbid associations with both PD and infrequent panic (IP), and b) investigate the nature of the relationships among these disorders. This community-based study included 97 adults who met DSM-III-R criteria for panic attacks compared with 97 matched controls. Psychiatric comorbidity was assessed using the SCID and SCL-90. Subjects with either PD or IP had higher rates of psychiatric comorbidity than controls. PD differed from IP only in its higher rate of phobic avoidance. Factor analysis found three factors: PD with phobic avoidance; substance abuse; major depression with obsessive compulsive disorder, social and simple phobias. Only phobic avoidance began secondary to panic onset. In conclusion, this study supports the PD-agoraphobia DSM-IV grouping while lending support to the common diathesis hypothesis for anxiety and affective disorders.


External fixator clamp reuse degrades clamp mechanical performance.
To determine the effects of clamp reuse for the Kirschner-Ehmer (KE); Securos; and the IMEX-SK clamp. Experimental bench test of mechanical properties. Specially designed fixtures were used to mechanically test 18 clamps of each type with respect to 6 mechanical variables: fixator pin slippage, connecting bar slippage, fixator pin rotation, connecting bar rotation, and clockwise and counterclockwise clamp-bolt axis pivot. Each clamp was tested 6 times for each variable at 7.68 Nm of clamp-bolt tightening torque. were compared using repeated measures ANOVA. Results- For the IMEX-SK clamp, a significant degradation in the force required to cause slippage was found for connecting bar slippage and fixator pin rotation; however, this clamp also had a significant increase in the force to initiate slippage for clockwise clamp-bolt axis pivot with reuse. The Securos clamp had significant degradation in connecting bar slippage, connecting bar rotation, and fixator pin rotation whereas the KE clamp had significant degradation in connecting bar slippage only. All 3 external fixator clamp types degraded in 1 or more movement variables in their ability to resist motion with reuse. The IMEX and Securos clamps were more subject to degradation than the KE clamp and this may have clinical importance for fixator composite rigidity. Fracture-reduction stability is related to the ability to resist motion within a clamp. The unpredictable nature of degradation we found cautions against repeated use. Clinicians should consider reuse of external fixator clamps with the knowledge that repeated use degrades clamp mechanical performance.


Meta analysis of propranolol effects on gastrointestinal hemorrhage in cirrhotic patients.
To assess the effects of propranolol as compared with placebo on gastrointestinal hemorrhage and total mortality in cirrhotic patients by using meta analysis of 20 published randomized clinical trials. A meta analysis of published randomized clinical trials was designed. Published articles were selected for study based on a computerized MEDLINE and a manual search of the bibliographies of relevant articles. Data from 20 relevant studies fulfilling the inclusion criteria were retrieved by means of computerized and manual search. The reported data were extracted on the basis of the intention-to-treat principle, and treatment effects were measured as risk differences between propranolol and placebo. Pooled estimates were computed according to a random-effects model. We evaluated the pooled efficacy of propranolol on the risk of gastrointestinal hemorrhage and the total mortality. A total of 1,859 patients were included in 20 trials, 931 in the propranolol groups and 928 as controls. Among the 652 patients with upper gastrointestinal tract hemorrhage, 261 patients were treated with propranolol, and 396 patients were treated with placebo or non-treated. Pooled risk differences of gastrointestinal hemorrhage were -18 % [95 % CI, -25 %, -10 %] in all trials, -11 % [95 % CI, -21 %, -1 %] in primary prevention trials, and -25 % [95 % CI, -39 %, -10 %] in secondary prevention trials. A total of 440 patients died, 188 in propranolol groups and 252 in control groups. Pooled risk differences of total death were -7 % [95 % CI, -12 %, -3 %] in all trials, -9 % [95 % CI, -18 %, -1 %] in primary prevention trials, and -5 % [95 % CI, -9 %, -1 %] in secondary prevention trials. Propranolol can markedly reduce the risks of both primary and recurrent gastrointestinal hemorrhage, and also the total mortality.


A Novel Method for Multi-subject fMRI Data Analysis: Independent Component Analysis with Clustering Embedded (ICA-CE).
The analysis of multi-subject functional magnetic resonance imaging (fMRI) data and the extraction of accurate brain functional networks (FNs) are of great importance. However, traditional independent component analysis (ICA) methods perform analysis on multi-subject fMRI data under the condition of known or assumed classes of subjects, which may decrease its ability to extract accurate individual brain FNs. Although a previous method named clusterwise ICA (C-ICA) clusters subjects and obtains shared FNs in group-level for each class, its clustering performance on complex data is not ideal. To address the issues, we propose a novel method called independent component analysis with clustering embedded (ICA-CE) that can achieve both the estimation of individual FNs and the clustering of subjects in an unsupervised or semi-supervised manner. Using the simulated data with different properties, ICA-CE achieved better clustering performance than group ICA followed by K-means and C-ICA, and the mean accuracy of extracted individual FNs obtained by ICA-CE was greater than 90%. Using the task-related fMRI data from Human Connectome Project (HCP), our method also achieved higher clustering accuracy, while extracting task-related class-specific FNs. In summary, ICA-CE is effective in estimating accurate brain FNs while achieving the clustering of multiple subjects.Clinical Relevance- Our method is promising in estimating accurate brain functional networks for patients with brain disorders and outputting related class label for each subject.


Human herpesvirus-6 encephalitis following chemotherapy induction for acute myelogenous leukemia.
We report a case of human herpesvirus-6 (HHV-6) encephalitis in a neutropenic patient who had undergone chemotherapy induction for acute myelogenous leukemia while on broad-spectrum antimicrobial therapy. The patient displayed symptoms of confusion, amnesia, and lethargy. Diagnosis was made via polymerase chain reaction analysis of cerebrospinal fluid. Electroencephalogram and magnetic resonance imaging of the brain were unremarkable. Following diagnosis, the patient was successfully treated with ganciclovir. HHV-6 encephalitis should be considered in immunocompromised patients who become encephalopathic.


[Non-invasive methods for the assessment of platelet, leukocyte, erythrocyte aggregation and coagulation hemostasis].
A non-invasive method for the study of platelet aggregation and formation of leukocyte-erythrocyte-platelet aggregates as well as certain hemostatic parameters is proposed. The method is based on the speckle-analysis of coherent light scattering from the surface of erythrocytes moving in an artificially isolated vessel segment. It was shown that light scattering index significantly correlated with ADP-, adrenalin-, or collagen-induced platelet aggregation, with the formation of leukocyte-erythrocyte or platelet-erythrocyte aggregates, and with the levels of fibrinogen, soluble fibrin-monomer complexes and related parameters. It is concluded that the proposed method for the study of hemostatic system can be used to roughly evaluate intensity of intravascular blood coagulation and probability of thrombosis.


Assessing the effectiveness of intubation as a challenge model in contagious bovine pleuropneumonia vaccine experiments.
A study was carried out to assess the effectiveness of a bronchoscope in administering a pathogenic field strain of Mycoplasma mycoides subsp. mycoides (MmmSC) in cattle challenge experiments. Out of 16 animals inoculated using the bronchoscope, 10 (62.2%) showed clinical disease as evidenced by fever and 15 (93.8%) displayed typical lesions of CBPP from which MmmSC was isolated. Serum samples collected weekly were tested by Complement Fixation Test (CFT) and competitive enzyme-linked immunosorbent assay (c-ELISA). Antibodies to MmmSC were detected in 10 out of the 16 animals by the CFT and 11 out of the 16 animals by c-ELISA. The onset of clinical disease was as early as 2 days post-inoculation, and most of the animals developed clinical disease 2 to 3 weeks post-infection. These results clearly demonstrate that nasotracheal inoculation of pathogenic strain of MmmSC with the aid of a bronchoscope can lead to early onset of clinical disease; similar to previous studies but with higher numbers of animals showing clinical disease. This is in contrast with previous studies where early clinical disease was observed in as little as 15% of inoculated animals. This nasotracheal inoculation method using a bronchoscope can, therefore, be adopted for use in experimental challenge infections of cattle. This method is found to be a better replacement to the contact transmission method whose drawback includes extra cost of donor animals and unpredictable rate and timing of transmission from intubated to challenge animals.


Effects of intense "stretching"-flexibility training on the mechanical profile of the knee extensors and on the range of motion of the hip joint.
The sample for the study involved 12 volunteer male, active but not specially trained secondary school students. They averaged 15.33 years with a mean height of 168.20 cm, and a mean mass of 55.08 kg. Changes, if any, in the mechanical properties (MVC, half-relaxation time, fast isometric contraction, concentric contraction of the knee extensors) and flexibility of the hip joints were studied. The subjects executed passive, purely slow stretching as well as range-of-motion flexibility exercises for the knee extensors and the hip joints for 7 weeks three times a week. Pre- and post-measurements for flexibility and stride frequency on the spot showed significant improvement as did half-relaxation time, fast isometric force development, and speed of concentric contractions when low loads were to be overcome. In addition to studies in which improvements reported were attributed to and related to myoelectrical, reflex, and connective tissue changes, in the present study it was concluded that stretching exercises influence intrinsic muscle mechanical character along with a simultaneous improvement in range of motion of the joints exercised.


The factors associated with progression of tricuspid regurgitation after left-sided double valve replacement in propensity score matched analysis.
This study aims to investigate the association of progression of tricuspid regurgitation following double-valve replacement by comparing the tricuspid valve repair and no repair groups, and to analyze outcomes of patients with non-repaired mild-to-moderate tricuspid regurgitation. Between January 2014 and September 2017, a total of 157 patients (74 males, 83 females; mean age: 51.7±13.7 years; range, 18 to 78 years) who underwent aortic and mitral valve replacements with/without concomitant tricuspid valve repair were retrospectively analyzed. The patients were divided into two groups: no-repair (n=78) and repair groups (n=79). The primary outcome measure was development of more than moderate tricuspid regurgitation during follow-up. The data were evaluated according to propensity score matched analysis. The progression of tricuspid regurgitation was significantly increased in the no-repair group (p=0.006). Rheumatic etiology was independently associated with the presence of postoperative moderateto- severe tricuspid regurgitation (p=0.004, odds ratio: 3.40). There was no statistically significant difference between the groups in terms of the potential complications and mortality and survival rates. A multivariable subgroup analysis for the baseline mild-to-moderate tricuspid regurgitation without repair showed that rheumatic etiology was an independent factor for the progression of postoperative tricuspid regurgitation (p=0.01). Our study results demonstrated that rheumatic etiology was an independent marker for increased tricuspid regurgitation and it was also independently associated with increased tricuspid regurgitation in patients with mild-to-moderate non-repaired patients. The degree of tricuspid regurgitation was improved in the repair group during follow-up.


Morphological and adhesive properties of Klebsiella pneumoniae biofilms.
The study of biofilm-forming ability of Gram-negative microflora has great practical importance for assessing the effectiveness of antibiotic therapy and finding new ways to diagnose and inhibit the growth of biofilms. This is because poor penetration of antibacterial drugs into the biofilm can lead to the selection of resistant strains and has a consequence evident by the occurrence of relapse of infection in animals. This study aimed to evaluate morphological and densitometric indicators of biofilm formation as well as adhesive properties of Klebsiella pneumoniae. K. pneumoniae was cultured at 37°C for 2-144 h in vitro. The specimens for optical microscopy were prepared by fixation with a 1:1 alcohol-ether mixture for 10 min and stained with a 0.5% solution of gentian violet for 2 min, and the optical density index was evaluated at a wavelength of 490 nm. Further, the adhesive properties of the microorganisms were determined at a concentration of 1 billion/ml and a suspension of ram erythrocytes at a concentration of 100 million/ml when cultured at 37°C for 24 h. Blood smears were prepared and stained with 0.5% gentian violet. K. pneumonia cultured at 37°C after 24 h on the meat peptone agar formed large, convex, mucous, and white colonies (d=3.0-6.0 mm). With the growth in the meat and peptone broth, uniform turbidity of the medium was observed. Analyzing the optical density indices (density, D), it was found that K. pneumoniae were good producers of biofilms (D=0.528±0.31). Data for indicators of adhesive properties of K. pneumoniae were as follows: Average adhesion index, 4.56±0.14; adhesion coefficient, 1.07±0.52; and adhesion index, 4.26±0.07. The studied bacteria had high adhesive activity. A direct correlation dependence (R=0.94) of the optical density of biofilms (D≥0.514-0.551) and AAI (4.15±0.28-4.76±0.75) was established. This study has demonstrated that K. pneumoniae had high adhesive activity, was strong producer of biofilms, and the optical density of the sample exceeded the optical density of the control by more than 4 times.


Ethnic socialization and the academic adjustment of adolescents from Mexican, Chinese, and European backgrounds.
Ethnic and generation differences in the frequency and types of ethnic socialization messages that 524 eleventh-grade adolescents from Mexican, Chinese, and European backgrounds received from their parents were examined. Results indicated that adolescents from both Mexican and Chinese backgrounds reported more cultural socialization and preparation for bias messages than their peers from European backgrounds. Chinese adolescents reported more promotion of mistrust messages than their peers with European backgrounds. Moreover, promotion of mistrust messages negatively predicted academic achievement, whereas positive cultural socialization messages accounted for the higher levels of motivation among adolescents from Chinese and Mexican backgrounds as compared with their equally achieving peers from European backgrounds.


Mind the snake: Fear detection relies on low spatial frequencies.
The privileged processing of threat stimuli, even in the absence of visual awareness, has been associated with a subcortical superior colliculus (SC)-pulvinar pathway to the amygdala, bypassing the visual cortex. However, this has been heavily disputed by studies showing that cortical activity cannot be ruled out in fear processing. A recent study using continuous flash suppression (CFS) showed that rapid detection of fear faces relies on high spatial frequencies, which involve cortical visual areas. In the present study, we also used CFS and manipulated spatial frequency in order to assess if more primitive fear stimuli-snakes-follow a similar trend. Our results show an advantage of snakes in accessing awareness based on low spatial frequency information, arguing in favor of the role of a SC-pulvinar pathway to the amygdala. (PsycINFO Database Record


[The indices of spiroergometry and tetrapolar rheography in patients with ischemic heart disease].
Indices of the central hemodynamics and stroke indices were assessed by means of spiroergometry and tetrapolar chest rheography were studied in 35 practically healthy persons and 45 patients with ischemic heart disease and a direct correlation between the indices of hemodynamics and the above methods was found. Spiroergometry may be used for evaluation of the hemodynamic parameters in patients with ischemic heart disease.


Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery.
The aim of the present study was to evaluate the overall treatment efficacy (tumor control, facial nerve function, complications) and quality of life for patients treated primarily for unilateral vestibular schwannomas of 30 mm or less, either by microsurgery or by gamma knife (GK) radiosurgery. The results for the two treatment groups are compared with each other, with main emphasis on the long-term quality of life. This is a retrospective study of 189 consecutive patients, 86 treated by microsurgery and 103 by gamma knife. The mean observation time was 5.9 years. All patients had a magnetic resonance imaging scan and clinical evaluation performed toward the end of the study. To evaluate the quality of life, we used two standardized questionnaires, the Glasgow Benefit Inventory and Short-Form 36. The questionnaires were sent to the 168 living patients. The reply rate was 83.3%. A total of 79.8% of the patients in the microsurgery group and 94.8% of the GK patients had a good facial nerve function (House-Brackmann Grade 1-2). Hearing was usually lost after microsurgery, whereas the GK patients had preserved hearing, which often became reduced over the years after the treatment. The treatment efficacy, defined as no need for additional treatment, was similar for the two treatment modalities. Quality of life was reduced compared with normative data, being most reduced in the microsurgery group. Some of the quality of life questions showed an association with facial nerve function and sex. Posttreatment facial nerve function, hearing, complication rates, and quality of life were all significantly in favor of GK radiosurgery.


Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas.
Protease inhibitors regulate a variety of physiological and pathological processes including angiogenesis, embryo implantation, intravascular fibrinolysis, wound healing, and tumor invasion. Tissue factor pathway inhibitor (TFPI) 2 is a Mr 32,000 Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. In this study, we determined the relative amounts of TFPI-2 in low-, intermediate-, and high-grade human glioma cell lines and tumor tissue samples. TFPI-2 protein and mRNA levels (measured by Western and Northern blotting) were highest in low-grade glioma cells (Hs683), lower in anaplastic astrocytoma cells (SW1088 and SW1783), and undetectable in high-grade glioma cells (SNB19). Analysis of TFPI-2 protein in human normal brain and in glioma tumor tissues for TFPI-2 revealed the highest levels in normal brain, lesser amounts in low-grade gliomas and anaplastic astrocytomas, and undetectable amounts in glioblastomas. In situ hybridization of TFPI-2 mRNA with normal brain tissues revealed the greatest positivity in neurons, with moderate positivity in both glial and endothelial cells and moderate, little, or no TFPI-2 mRNA in low-grade glioma, anaplastic astrocytoma, and glioblastoma tumor tissue samples, respectively. We also found that recombinant TFPI-2 inhibited the invasiveness of SNB19 glioblastoma cells in a Matrigel assay in a dose-dependent manner. Collectively, these results suggest that TFPI-2 has a regulatory role in the invasiveness of gliomas in vitro and in vivo.


The Incidence of Primary vs Secondary Focal Segmental Glomerulosclerosis: A Clinicopathologic Study.
To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS. Olmsted County adult residents with native kidney biopsy from January 1, 1994, through December 31, 2013, and FSGS as the only glomerulopathy were identified. The clinical and pathologic characterstics of primary and secondary FSGS were described and compared, and incidence rates were calculated. Of 370 adults biopsied, 281 had glomerular diseases, of which 46 (16%) had FSGS. From 1994-2003 to 2004-2013, there were significant increases in kidney biopsy rates (14.7 [95% CI, 12.1-17.3] vs 22.9 [95% CI, 20.0-25.7] per 100,000 person-years, 17% increase per 5 years; P<.001) and total FSGS rates (1.4 [95% CI, 0.6-2.2] vs 3.2 [95% CI, 2.1-4.3] per 100,000 person-years, 41% increase per 5 years; P=.02). Compared with patients with limited foot process effacement (<80%), patients with diffuse effacement (≥80%) without an identifiable cause had lower serum albumin levels (P<.001), had higher proteinuria (P<.001), and were more likely to have nephrotic syndrome (100% vs 4%; P<.001). Patients with diffuse effacement without an identifiable cause were classified as primary FSGS, which accounted for 3 of 12 patients (25%) during 1994-2003 and 9 of 34 (26%) during 2004-2013. Although the incidence of FSGS has increased, the proportions of primary and secondary FSGS have remained stable.


Spiers Memorial Lecture. Carbon nanostructures by macromolecular design - from branched polyphenylenes to nanographenes and graphene nanoribbons.
Nanographenes (NGs) and graphene nanoribbons (GNRs) are unique connectors between the domains of 1D-conjugated polymers and 2D-graphenes. They can be synthesized with high precision by oxidative flattening processes from dendritic or branched 3D-polyphenylene precursors. Their size, shape and edge type enable not only accurate control of classical (opto)electronic properties, but also access to unprecedented high-spin structures and exotic quantum states. NGs and GNRs serve as active components of devices such as field-effect transistors and as ideal objects for nanoscience. This field of research includes their synthesis after the deposition of suitable monomers on surfaces. An additional advantage of this novel concept is in situ monitoring of the reactions by scanning tunnelling microscopy and electronic characterization of the products by scanning tunnelling spectroscopy.


Role of algal eukaryotes in subtidal columnar stromatolite formation.
Columnar stromatolites were abundant and widespread in the Proterozoic but are exceedingly rare in modern seas. Consequently, the stromatolites at Hamelin Pool in Shark Bay, Western Australia, have been widely interpreted as unique modern analogs of ancient stromatolites constructed by complex communities of cyanobacteria. However, the Shark Bay columnar stromatolites contain sediment that is unusually coarse for stromatolites both ancient and modern, and the subtidal columnar stromatolites have a significant component of algal eukaryotes dominated by motile diatoms with mucilaginous tubes. This suggests that Shark Bay columnar stromatolites are not strict analogs for most ancient cyanobacterial stromatolites, least of all for those from subtidal environments. We argue that algal eukaryotes may play a substantial role in the formation and maintenance of subtidal columnar stromatolites at Shark Bay and are capable of trapping coarse sediment. In contrast, cyanobacteria have difficulty in trapping coarse sediment and produce essentially fine-grained stromatolites. We propose that there are two major types or end members of Recent marine stromatolites: (i) eualgal-cyanobacterial stromatolites that are generally coarse-grained, and (ii) cyanobacterial stromatolites that are generally fine-grained.


The Role of the FMN-Domain of Human Cytochrome P450 Oxidoreductase in Its Promiscuous Interactions With Structurally Diverse Redox Partners.
NADPH cytochrome P450 oxidoreductase (CPR) is the obligatory electron supplier that sustains the activity of microsomal cytochrome P450 (CYP) enzymes. The variant nature of the isoform-specific proximal interface of microsomal CYPs indicates that CPR is capable of multiple degenerated interactions with CYPs for electron transfer, through different binding mechanisms, and which are still not well-understood. Recently, we showed that CPR dynamics allows formation of open conformations that can be sampled by its structurally diverse redox partners in a CYP-isoform dependent manner. To further investigate the role of the CPR FMN-domain in effective binding of CPR to its diverse acceptors and to clarify the underlying molecular mechanisms, five different CPR-FMN-domain random mutant libraries were created. These libraries were screened for mutants with increased activity when combined with specific CYP-isoforms. Seven CPR-FMN-domain mutants were identified, supporting a gain in activity for CYP1A2 (P117H, G144C, A229T), 2A6 (P117L/L125V, G175D, H183Y), or 3A4 (N151D). Effects were evaluated using extended enzyme kinetic analysis, cytochrome b 5 competition, ionic strength effect on CYP activity, and structural analysis. Mutated residues were located either in or adjacent to several acidic amino acid stretches - formerly indicated to be involved in CPR:CYP interactions - or close to two tyrosine residues suggested to be involved in FMN binding. Several of the identified positions co-localize with mutations found in naturally occurring CPR variants that were previously shown to cause CYP-isoform-dependent effects. The mutations do not seem to significantly alter the geometry of the FMN-domain but are likely to cause very subtle alterations leading to improved interaction with a specific CYP. Overall, these data suggest that CYPs interact with CPR using an isoform specific combination of several binding motifs of the FMN-domain.


The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung.
Because small-cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research. The pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns Laboratory) and triple knockouts from the Sage, MacPherson, and Jacks laboratories (double knockout model plus loss of p130 [Sage laboratory] or loss of Pten [MacPherson and Jacks laboratories]). In addition, a GEMM with constitutive co-expression of SV40 large T antigen and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory were included. The lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large-cell NE cell carcinoma in varying proportions. Occasional adeno- or large-cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/T antigen model many peripherally arising non-small-cell lung carcinoma tumors having varying degrees of NE marker expression were present (non-small-cell lung carcinoma-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations. The five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer.


Factors Associated with Geographical Variability of Antimicrobial Use in Japan.
Evidence regarding the factors affecting the geographical variation of antimicrobial use (AMU) is relatively scarce. This study aimed to evaluate factors potentially associated with geographical variability of AMU per day per 1000 habitants in the 47 prefectures of Japan. This is an observational ecological study using the Japanese national database in 2019. The outcome was the defined daily doses per 1000 inhabitants per day by prefecture. Multivariable negative binomial regression analysis was conducted using patient- and physician-level variables. The study included 605,391,054 defined daily doses of AMU in 2019 from the 47 prefectures. In the multivariable negative binomial regression analyses for the outcome of total AMU, the proportion of female individuals (adjusted rate ratio [aRR] 1.04 [1.01-1.08] per 1% increase, p = 0.021), the proportion of upper secondary graduates going to further education (aRR 1.01 [1.00-1.01] per 1% increase, p = 0.005), and the annual number of diagnoses related to upper respiratory infections (URIs) per 1000 inhabitants per day (aRR 1.21 [1.10-1.34], p < 0.001) were significantly correlated with total AMU. In this ecological study, the variability of total AMU by Japanese prefecture was associated with the proportion of female individuals, education level, and the number of URI diagnoses per population. The results suggest the potential need for additional stewardship efforts to reduce unnecessary antimicrobial prescriptions for URI.


Effects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice.
The potential effects of Bisphenol A (BPA) on peripheral insulin resistance have recently gained more attention, however, its functions on brain insulin resistance are still unknown. The aim of the present study was to investigate the effects of BPA on insulin signaling and glucose transport in mouse brain. The male mice were administrated of 100 μg/kg/day BPA or vehicle for 15 days then challenged with glucose and insulin tolerance tests. The insulin levels were detected with radioimmunoassay (RIA), and the insulin signaling pathways were investigated by Western blot. Our results revealed that BPA significantly increased peripheral plasma insulin levels, and decreased the insulin signals including phosphorylated insulin receptor (p-IR), phosphorylated insulin receptor substrate 1 (p-IRS1), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated extracellular regulated protein kinases (p-ERK1/2) in the brain, though insulin expression in both hippocampus and profrontal cortex was increased. In parallel, BPA exposure might contribute to glucose transport disturbance in the brain since the expression of glucose transporters were markedly decreased. In conclusion, BPA exposure perturbs the insulin signaling and glucose transport in the brain, therefore, it might be a risk factor for brain insulin resistance.


Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB.
In the current work, we carried out a mechanistic study on the cytotoxicity of two compounds, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-N-methyl-benzamide (t-AUCMB) and trans-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (t-MTUCB), that are structurally similar to sorafenib. These compounds show strong cytotoxic responses in various cancer cell lines, despite significant differences in the induction of apoptotic events such as caspase activation and lactate dehydrogenase release in hepatoma cells. Both compounds induce autophagosome formation and LC3I cleavage, but there was little observable effect on mTORC1 or the downstream targets, S6K1 and 4E-binding protein. In addition, there was an increase in the activity of upstream signaling through the IRS1/PI3K/Akt-signaling pathway, suggesting that, unlike sorafenib, both compounds induce mammalian target of rapamycin (mTOR)-independent autophagy. The autophagy observed correlates with mitochondrial membrane depolarization, apoptosis-inducing factor release, and oxidative stress-induced glutathione depletion. However, there were no observable changes in the endoplasmic reticulum-stress markers such as binding immunoglobulin protein, inositol-requiring enzyme-α, phosphorylated eukaryotic initiation factor 2, and the lipid peroxidation marker, 4-hydroxynonenal, suggesting endoplasmic reticulum-independent oxidative stress. Finally, these compounds do not have the multikinase inhibitory activity of sorafenib, which may be reflected in their difference in the ability to halt cell cycle progression compared with sorafenib. Our findings indicate that both compounds have anticancer effects comparable with sorafenib in multiple cell lines, but they induce significant differences in apoptotic responses and appear to induce mTOR-independent autophagy. t-AUCMB and t-MTUCB represent novel chemical probes that are capable of inducing mTOR-independent autophagy and apoptosis to differing degrees, and may thus be potential tools for further understanding the link between these two cellular stress responses.


Comparative glycomic profiling of isotopically permethylated N-glycans by liquid chromatography/electrospray ionization mass spectrometry.
Mass spectrometry based comparative glycomics is essential for disease biomarker discovery. However, developing a reliable quantification method is still a challenging task. We here report an isotopic labeling strategy employing stable isotopic iodomethane for comparative glycomic profiling by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS). N-Glycans released from model glycoproteins and blood serum samples were permethylated with iodomethane ('light') and iodomethane-d1 or -d3 ('heavy') reagents. Permethylated samples were then mixed at equal volumes prior to LC/ESI-MS analysis. Peak intensity ratios of N-glycans isotopically permethylated (Heavy/Light, H/L) were almost equal to the theoretical values. Observed differences were mainly related to the purity of 'heavy' iodomethane reagents (iodomethane-d1 or -d3). The data suggested the efficacy of this strategy to simultaneously quantify N-glycans derived from biological samples representing different cohorts. Accordingly, this strategy is effective in comparing multiple samples in a single LC/ESI-MS analysis. The potential of this strategy for defining glycomic differences in blood serum samples representing different esophageal diseases was explored. LC/ESI-MS comparative glycomic profiling of isotopically permethylated N-glycans derived from biological samples and glycoproteins reliably defined glycan changes associated with biological conditions or glycoproteins expression. As a biological application, this strategy permitted the reliable quantification of glycomic changes associated with different esophageal diseases, including high grade dysplasia, Barrett's disease, and esophageal adenocarcinoma.


99Tcm-MAA lung scintigraphy in patients with Behçet's disease: its value and correlation with clinical course and other diagnostic modalities.
Behçet's disease, initially described as local vasculitis involving the oral, genital mucosa and eyes, can affect many organ systems with a varying clinical course. Pulmonary lesions associated with Behçet's disease are rare and reported to have a prevalence of 1.0-7.7%. In this prospective study, 29 patients aged 16-60 years (mean +/- s: 34 +/- 10.5) were investigated for pulmonary involvement with direct radiography, computerized tomography (CT) and intravenous digital subtraction angiography. Lung scintigraphy was also performed to determine its diagnostic value. In addition, patients had a fibreoptic bronchoscopic examination, spirometric test, carbon monoxide diffusion test and methacholine test. Of the 29 patients with Behçet's disease, 17 had pulmonary involvement. The diagnostic criteria for pulmonary vasculitis and tracheobronchial tree involvement were: (1) hilar vascular prominence or mass, new alveolar and reticulonodular infiltrates on chest X-ray; (2) aphthous lesions, bleeding ulcerations, inflamed mucosal appearance on bronchoscopy; (3) vascular thrombosis or aneurysms on CT; (4) occlusion or aneurysms of the main pulmonary arteries or its branches. The value of lung scintigraphy and its correlation with other imaging modalities were investigated to determine if a lung perfusion scan alone can be used to detect pulmonary involvement in Behçet's disease. Twenty-six patients were investigated with lung scintigraphy. Thirteen of 14 patients with lung involvement were identified. Perfusion lung scintigraphy provided true diagnostic information in 96% of our patients. In eight patients without pulmonary involvement, the lung scans were normal. Although DSA specifically demonstrates pulmonary aneurysms, it involves administration of contrast media and cannot show abnormalities distal to the third pulmonary arterial branches. Although vasculitis caused by collagen disorders is physiologically indistinguishable from pulmonary emboli, most perfusion defects resolve within 3 months, which can be used as a differential diagnostic criterion in the appropriate clinical setting. Therefore, pulmonary perfusion imaging can be used to screen patients suspected of having lung involvement, especially in the absence of thrombophlebitis. In patients with thrombophlebitis, a repeat examination at 3 months is recommended to differentiate pulmonary involvement from pulmonary embolism.


Interventions for hirsutism (excluding laser and photoepilation therapy alone).
Hirsutism occurs in 5% to 10% of women of reproductive age when there is excessive terminal hair growth in androgen-sensitive areas (male pattern). It is a distressing disorder with a major impact on quality of life. The most common cause is polycystic ovary syndrome. There are many treatment options, but it is not clear which are most effective. To assess the effects of interventions (except laser and light-based therapies alone) for hirsutism. We searched the Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), and five trials registers, and checked reference lists of included studies for additional trials. The last search was in June 2014. Randomised controlled trials (RCTs) in hirsute women with polycystic ovary syndrome, idiopathic hirsutism, or idiopathic hyperandrogenism. Two independent authors carried out study selection, data extraction, 'Risk of bias' assessment, and analyses. We included 157 studies (sample size 30 to 80) comprising 10,550 women (mean age 25 years). The majority of studies (123/157) were 'high', 30 'unclear', and four 'low' risk of bias. Lack of blinding was the most frequent source of bias. Treatment duration was six to 12 months. Forty-eight studies provided no usable or retrievable data, i.e. lack of separate data for hirsute women, conference proceedings, and losses to follow-up above 40%.Primary outcomes, 'participant-reported improvement of hirsutism' and 'change in health-related quality of life', were addressed in few studies, and adverse events in only half. In most comparisons there was insufficient evidence to determine if the number of reported adverse events differed. These included known adverse events: gastrointestinal discomfort, breast tenderness, reduced libido, dry skin (flutamide and finasteride); irregular bleeding (spironolactone); nausea, diarrhoea, bloating (metformin); hot flushes, decreased libido, vaginal dryness, headaches (gonadotropin-releasing hormone (GnRH) analogues)).Clinician's evaluation of hirsutism and change in androgen levels were addressed in most comparisons, change in body mass index (BMI) and improvement of other clinical signs of hyperandrogenism in one-third of studies.The quality of evidence was moderate to very low for most outcomes.There was low quality evidence for the effect of two oral contraceptive pills (OCPs) (ethinyl estradiol + cyproterone acetate versus ethinyl estradiol + desogestrel) on change from baseline of Ferriman-Gallwey scores. The mean difference (MD) was -1.84 (95% confidence interval (CI) -3.86 to 0.18).There was very low quality evidence that flutamide 250 mg, twice daily, reduced Ferriman-Gallwey scores more effectively than placebo (MD -7.60, 95% CI -10.53 to -4.67 and MD -7.20, 95% CI -10.15 to -4.25). Participants' evaluations in one study with 20 participants confirmed these results (risk ratio (RR) 17.00, 95% CI 1.11 to 259.87).Spironolactone 100 mg daily was more effective than placebo in reducing Ferriman-Gallwey scores (MD -7.69, 95% CI -10.12 to -5.26) (low quality evidence). It showed similar effectiveness to flutamide in two studies (MD -1.90, 95% CI -5.01 to 1.21 and MD 0.49, 95% CI -1.99 to 2.97) (very low quality evidence), as well as to finasteride in two studies (MD 1.49, 95% CI -0.58 to 3.56 and MD 0.40, 95% CI -1.18 to 1.98) (low quality evidence).Although there was very low quality evidence of a difference in reduction of Ferriman-Gallwey scores for finasteride 5 mg to 7.5 mg daily versus placebo (MD -5.73, 95% CI -6.87 to -4.58), it was unlikely it was clinically meaningful. These results were reinforced by participants' assessments (RR 2.06, 95% CI 0.99 to 4.29 and RR 11.00, 95% CI 0.69 to 175.86). However, finasteride showed inconsistent results in comparisons with other treatments, and no firm conclusions could be reached.Metformin demonstrated no benefit over placebo in reduction of Ferriman-Gallwey scores (MD 0.05, 95% CI -1.02 to 1.12), but the quality of evidence was low. Results regarding the effectiveness of GnRH analogues were inconsistent, varying from minimal to important improvements.We were unable to pool data for OCPs with cyproterone acetate 20 mg to 100 mg due to clinical and methodological heterogeneity between studies. However, addition of cyproterone acetate to OCPs provided greater reductions in Ferriman-Gallwey scores.Two studies, comparing finasteride 5 mg and spironolactone 100 mg, did not show differences in participant assessments and reduction of Ferriman-Gallwey scores (low quality evidence). Ferriman-Gallwey scores from three studies comparing flutamide versus metformin could not be pooled (I² = 62%). One study comparing flutamide 250 mg twice daily with metformin 850 mg twice daily for 12 months, which reached a higher cumulative dosage than two other studies evaluating this comparison, showed flutamide to be more effective (MD -6.30, 95% CI -9.83 to -2.77) (very low quality evidence). Data showing reductions in Ferriman-Gallwey scores could not be pooled for four studies comparing finasteride with flutamide as the results were inconsistent (I² = 67%).Studies examining effects of hypocaloric diets reported reductions in BMI, but which did not result in reductions in Ferriman-Gallwey scores. Although certain cosmetic measures are commonly used, we did not identify any relevant RCTs. Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects.Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other. Outcomes should be based on standardised scales of participants' assessment of treatment efficacy, with a greater emphasis on change in quality of life as a result of treatment.


Expression of type IV collagen in different histological grades of oral squamous cell carcinoma: an immunohistochemical study.
The aim of this study was to evaluate the expression of type IV collagen in three histological grades of oral squamous cell carcinoma (SCC) in comparison with that in normal oral mucosa, to determine whether this protein can be used as a marker in early detection of the biological behavior of phenotypically altered cells. The staining intensity, staining pattern, and distribution mode for type IV were compared among the four groups by two pathologists, and the differences between observers and disease groups were statistically analyzed by Chi-square test or Fisher's exact test. The type IV staining intensity was more enhanced in well-differentiated (w) SCC than poorly-differentiated (p) SCC (P = 0.004). The staining was more linear (P = 0.001) and continuous (P = 0.003) in early invasive SCCs than in highly invasive SCCs. Its distribution was more continuous in wSCC than in less differentiated SCC (P = 0.003). There were statistically significant differences in the staining intensity between wSCC and pSCC (P = 0.005) or between wSCC and moderately differentiated SSC (P = 0.003) and in the staining pattern between wSCC and pSCC (P = 0.001). The results indicated that there was a direct relationship between the presence of type IV collagen and the differentiation degree of SCC cells and thus that SCC cells loose their capability to form the basement membrane as they become less differentiated.


Growth Hormone Deficiency in Childhood Intracranial Germ Cell Tumor Survivors.
Intracranial germ cell tumor (iGCT) survivors have multiple risk factors for growth hormone (GH) deficiency, a commonly reported late effect in childhood cancer survivors. The objective of this study is to examine the prevalence of GH deficiency among childhood iGCT survivors. Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), a case parent triad study conducted using the Children's Oncology Group registry protocols, including 216 cases with iGCTs. Data on late effects and outcomes are available for 129 iGCT cases who consented for a follow-up study including a self-administered questionnaire and medical record retrieval. GH deficiency was identified via self-report and validated through medical record review. Chi-squared and Fisher's exact tests were used to examine cases with GH deficiency predating iGCT detection. Logistic regression was used to identify predictors of GH deficiency as a late effect. Of 129 iGCT cases who participated in the late effects study, 45% had GH deficiency; 18% had GH deficiency predating the iGCT and 27% developed GH deficiency within a median of 19 months after diagnosis. Younger age at diagnosis, suprasellar location, and higher radiation doses were associated with GH deficiency as a late effect. GH deficiency is highly prevalent as an early clinical sign for iGCT and frequently arises as an early late effect after treatment. Additional investigation is needed to address earlier detection and treatment for this highly prevalent late effect in iGCT survivors.


Establishing a National Cardiovascular Disease Surveillance System in the United States Using Electronic Health Record Data: Key Strengths and Limitations.
Cardiovascular disease surveillance involves quantifying the evolving population-level burden of cardiovascular outcomes and risk factors as a data-driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more "national" surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care-seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information-gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.


Exploring the nexus between physical environments, resident preferences, and usage frequency of community centers: Evidence from two Korean neighborhoods in Seoul.
Community centers offer a public space for physical activities, attracting residents with diverse interests and abilities, and promoting social interaction and connection, which in turn enhances individuals' physical and mental fitness and fosters a sense of community. When exploring the correlation between community space accessibility and usage frequency, it is crucial to consider empirical evidence and resident preferences. Nevertheless, the role of physical environments in determining community center usage frequency, while also considering residents' inclination for effortless access, remains unclear. This study investigated the impact of resident preferences and satisfaction with the accessibility of community centers and physical environments on usage frequency, addressing a gap in previous research. Structural equation models were utilized to analyze a household drop-off survey consisting of 186 residents gathered from two neighborhoods in Korea. The results revealed that while the preference for easy access to community centers did not have a substantial effect on their usage frequency, satisfaction with easy access to such centers was positively linked to usage frequency. Furthermore, the perception of physical environments as being walkable and having a diverse range of amenities was associated with a higher frequency of community center usage. These findings have policy implications as they can help increase the usage frequency of community centers and enhance overall well-being in regenerated neighborhoods.


Lateral diffusion of membrane-spanning and glycosylphosphatidylinositol-linked proteins: toward establishing rules governing the lateral mobility of membrane proteins.
In the plasma membrane of animal cells, many membrane-spanning proteins exhibit lower lateral mobilities than glycosylphosphatidylinositol (GPI)-linked proteins. To determine if the GPI linkage was a major determinant of the high lateral mobility of these proteins, we measured the lateral diffusion of chimeric membrane proteins composed of normally transmembrane proteins that were converted to GPI-linked proteins, or GPI-linked proteins that were converted to membrane-spanning proteins. These studies indicate that GPI linkage contributes only marginally (approximately twofold) to the higher mobility of several GPI-linked proteins. The major determinant of the high mobility of these proteins resides instead in the extracellular domain. We propose that lack of interaction of the extracellular domain of this protein class with other cell surface components allows diffusion that is constrained only by the diffusion of the membrane anchor. In contrast, cell surface interactions of the ectodomain of membrane-spanning proteins exemplified by the vesicular stomatitis virus G glycoprotein reduces their lateral diffusion coefficients by nearly 10-fold with respect to many GPI-linked proteins.


Discovery of new type I toxin-antitoxin systems adjacent to CRISPR arrays in Clostridium difficile.
Clostridium difficile, a major human enteropathogen, must cope with foreign DNA invaders and multiple stress factors inside the host. We have recently provided an experimental evidence of defensive function of the C. difficile CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) system important for its survival within phage-rich gut communities. Here, we describe the identification of type I toxin-antitoxin (TA) systems with the first functional antisense RNAs in this pathogen. Through the analysis of deep-sequencing data, we demonstrate the general co-localization with CRISPR arrays for the majority of sequenced C. difficile strains. We provide a detailed characterization of the overlapping convergent transcripts for three selected TA pairs. The toxic nature of small membrane proteins is demonstrated by the growth arrest induced by their overexpression. The co-expression of antisense RNA acting as an antitoxin prevented this growth defect. Co-regulation of CRISPR-Cas and type I TA genes by the general stress response Sigma B and biofilm-related factors further suggests a possible link between these systems with a role in recurrent C. difficile infections. Our results provide the first description of genomic links between CRISPR and type I TA systems within defense islands in line with recently emerged concept of functional coupling of immunity and cell dormancy systems in prokaryotes.


Molecular cloning and targeting of a fibrillarin homolog from Arabidopsis.
Fibrillarin is a nucleolar protein known to be involved in the processing of ribosomal RNA precursors. We isolated AtFbr1, a cDNA encoding a homolog of fibrillarin in Arabidopsis. The cDNA is 1.2 kb in size and encodes a polypeptide of 310 amino acid residues with a molecular mass of 33 kD. AtFbr1 is expressed at high levels in the flower and root tissue and at a slightly lower level in leaf tissue, whereas it was nearly undetectable in siliques. Expression of AtFbr1 was compared with that of the FLP (fibrillarin-like protein) gene identified by the Arabidopsis genome project. Abscisic acid treatment resulted in the down-regulation of the expression of both AtFbr1 and FLP genes in seedlings, although the degree of suppression was higher for FLP than for AtFbr1. In addition, the expression level of FLP decreased with the age of the seedlings, whereas AtFbr1 did not exhibit any detectable change. The subcellular localization of AtFbrl was studied with an in vivo targeting approach using a fusion protein, and was found to be correctly targeted to the nucleolus in protoplasts when expressed as a green fluorescent fusion protein (GFP). Deletion experiments showed that the N-terminal glycine- and arginine-rich region is necessary and sufficient to target AtFbr1 to the nucleolus.


(-)-Epigallocatechin-3-Gallate Reduces Perfluorodecanoic Acid-Exacerbated Adiposity and Hepatic Lipid Accumulation in High-Fat Diet-Fed Male C57BL/6J Mice.
Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase-1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.


Highly Dispersed X/SiO(2) and C/X/SiO(2) (X=Alumina, Titania, Alumina/Titania) in the Gas and Liquid Media.
Fumed oxides, such as silica, alumina, titania, and mixed X/silicas (X=Al(2)O(3) (AS), TiO(2) (TS), CVD-TiO(2), Al(2)O(3)/TiO(2) (AST)), pristine or covered by carbon deposits formed due to pyrolysis of cyclohexene, were studied using nitrogen adsorption-desorption, photon correlation spectroscopy particle sizing, and electrophoresis. A significant influence of the nature of surface-active sites and structural features of oxides (individual silica, mixed fumed, or prepared using chemical vapor deposition (CVD)) on the pyrolysis of cyclohexene is observed with respect to the pore size distributions due to differences between primary particles in aggregates and on their outer surfaces in the filling of channels by pyrocarbon, resulting also in a decrease in fractal dimension. Structural characteristics and dependences of the particle size distribution and electrokinetic potential of X/SiO(2) and C/X/SiO(2) on the pH of aqueous suspensions suggest that the carbon deposit covers mainly acidic sites at the X/SiO(2) interfaces and X phase patches possessing catalytic activity in pyrolysis, as the negative charge of particles is reduced by pyrocarbon grafting. Copyright 2000 Academic Press.


The aggregation of isolated human platelets in the presence of lipoproteins and prostacyclin.
Addition of prostacyclin (PGI2) temporarily inhibits platelet aggregation and permits the isolation of platelets free from plasma proteins, which have the same sensitivity as those in plasma [Moncada, Radomski & Vargas (1982) Br. J. Pharmacol. 75, 165P]. By using a modification of this technique we have established that platelets isolated from normal subjects aggregate more readily in response to ADP and adrenaline when physiological concentrations of low-density lipoproteins (LDL) are present. At high LDL concentrations spontaneous aggregation occurs. High-density lipoproteins (HDL) and very-low-density lipoproteins (VLDL) had no effect on agonist-induced platelet aggregation at normal concentrations, but HDL sensitized at higher concentrations. These effects by lipoproteins are not accompanied by changes in platelet lipid content. Cyclohexanedione treatment of LDL to modify apolipoproteins appeared to abolish the sensitization effect, indicating that binding to receptors was essential for the effects of LDL. LDL, but not HDL, overcame the inhibitory effect of PGI2 on platelet aggregation, except at very high concentrations of PGI2. PGI2 raised the cyclic AMP content of isolated platelets, but LDL only partially prevented this rise. These results suggest that LDL may have a greater role in platelet aggregation than previously recognized and may also regulate effects of PGI2. These findings may be of relevance to an understanding of cardiovascular diseases.