Albumin-induced coagulopathy is less severe and more effectively reversed with fibrinogen concentrate than is synthetic colloid-induced coagulopathy.
Synthetic colloids cause dilutional coagulopathy. The aims of our study were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared to synthetic colloids, and the comparative effectiveness of fibrinogen concentrate to reverse coagulopathy following dilution with these solutions. Coagulation was assessed with rotational thrombelastometry after stimulation with tissue factor (EXTEM) and in the presence of a platelet inhibitor (FIBTEM). With EXTEM, clotting time (CT), clot formation time CFT), alpha angle (AA) and maximum clot firmness (MCF) were recorded. With FIBTEM, only MCF was recorded. These parameters were assessed ex vivo in blood from 10 healthy volunteers; diluted 1:1 with either saline, Ringer's acetate, buffered/unbuffered hydroxyethyl starch, buffered/unbuffered dextran (synthetic colloids) or 5% albumin. Samples were analyzed before/after addition of fibrinogen concentrate. FIBTEM MCF decreased significantly upon dilution (> 50% reduced) with all colloid solutions (p ≤ 0.02), although a significantly greater coagulopathic effect was seen for samples diluted with synthetic colloids versus albumin (p ≤ 0.001). A significant reduction in the platelet component of clot strength (EXTEM MCF - FIBTEM MCF) was seen for samples diluted with synthetic colloids (p < 0.001) but not albumin (p = 0.10). Following addition of fibrinogen, FIBTEM MCF, EXTEM MCF and AA were significantly higher, and CFT was significantly shorter in samples diluted with albumin versus those treated with synthetic colloids (p ≤ 0.001). Hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids. In addition, albumin-induced coagulopathy was more effectively reversed following addition of fibrinogen concentrate compared with coagulopathy induced by synthetic colloids.


Emergence of a new Neisseria meningitidis clonal complex 11 lineage 11.2 clade as an effective urogenital pathogen.
Neisseria meningitidis (Nm) clonal complex 11 (cc11) lineage is a hypervirulent pathogen responsible for outbreaks of invasive meningococcal disease, including among men who have sex with men, and is increasingly associated with urogenital infections. Recently, clusters of Nm urethritis have emerged primarily among heterosexual males in the United States. We determined that nonencapsulated meningococcal isolates from an ongoing Nm urethritis outbreak among epidemiologically unrelated men in Columbus, Ohio, are linked to increased Nm urethritis cases in multiple US cities, including Atlanta and Indianapolis, and that they form a unique clade (the US Nm urethritis clade, US_NmUC). The isolates belonged to the cc11 lineage 11.2/ET-15 with fine type of PorA P1.5-1, 10-8; FetA F3-6; PorB 2-2 and express a unique FHbp allele. A common molecular fingerprint of US_NmUC isolates was an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. This resulted in the loss of encapsulation and intrinsic lipooligosaccharide sialylation that may promote adherence to mucosal surfaces. Furthermore, we detected an IS1301-mediated inversion of an ∼20-kb sequence near the cps locus. Surprisingly, these isolates had acquired by gene conversion the complete gonococcal denitrification norB-aniA gene cassette, and strains grow well anaerobically. The cc11 US_NmUC isolates causing urethritis clusters in the United States may have adapted to a urogenital environment by loss of capsule and gene conversion of the Neisseria gonorrheae norB-aniA cassette promoting anaerobic growth.


Submuscular versus subcutaneous pectoral implantation of cardioverter-defibrillators: effect on high voltage pathway impedance and defibrillation efficacy.
Implantable cardioverter-defibrillator (ICD) pulse generators are now routinely positioned in a pectoral location, either submuscularly (under the pectoralis muscles) or subcutaneously (over the pectoralis muscles). Furthermore, in current ICDs, the generator shield usually participates in the defibrillation energy pathway ("hot can"). Consequently, the precise generator location could affect defibrillation system efficacy. To assess this issue, we compared high voltage pathway impedance and defibrillation threshold (DFT) in 20 patients undergoing submuscular and 46 patients undergoing subcutaneous pectoral implantation of an Angeion Sentinel ICD and an AngeFlex dual-coil defibrillation lead. Measurements were performed at time of ICD implant, pre-hospital discharge, and 1, 3 and/or 6 months later. Following induction of ventricular fibrillation, 569 biphasic waveform shocks were delivered between the generator shield and either the distal defibrillation coil (RV/can configuration) or both proximal and distal coils (RV/SVC/can configuration). Impedance differences between submuscular and subcutaneous implants were approximately 3-4 Ohms (p value of 0.132 to < 0.001 depending on time of follow-up and lead configuration). A significant increase in impedance over time was noted independent of implant location and lead configuration. The DFT at implant or pre-discharge was assessed in 27 individuals, and was 9.9 +/- 3.8 J in 8 patients in the submuscular group, and 7.4 +/- 3.3 J in 19 patients in the subcutaneous group (p = 0.057). In conclusion, anatomic location of a "hot can" ICD generator (submuscular versus subcutaneous) influences impedance to defibrillation current, but the impact is of small magnitude and does not appear to result in clinically important differences in DFT.


Janus microdimer swimming in an oscillating magnetic field.
Artificial microswimmers powered by magnetic fields have numerous applications, such as drug delivery, biosensing for minimally invasive medicine and environmental remediation. Recently, a Janus microdimer surface walker that can be propelled by an oscillating magnetic field near a surface was reported by Li et al. (Adv. Funct. Mater. 28, 1706066. (doi:10.1002/adfm.201706066)). To clarify the mechanism for the surface walker, we numerically studied in detail a Janus microdimer swimming near a wall actuated by an oscillating magnetic field. The results showed that a Janus microdimer in an oscillating magnetic field can produce magnetic torque in the y-direction, which eventually propels the Janus microdimer along the x-direction near a wall. Furthermore, we found that the Janus microdimer can also move along a special direction in an oscillating magnetic field with two orientations without a wall. The knowledge obtained in this study is fundamental for understanding the interactions between a Janus microdimer and surfaces in an oscillating magnetic field and is useful for controlling Janus microdimer motion with or without a wall.


The morphogenesis of bone in replicas of porous hydroxyapatite obtained from conversion of calcium carbonate exoskeletons of coral.
The morphogenesis of bone in a porous hydroxyapatite substratum was studied after intramuscular implantation in adult primates. Replicas of porous hydroxyapatite that had been obtained after hydrothermal conversion of the calcium carbonate exoskeleton of coral (genus Goniopora) were implanted intramuscularly in twenty-four adult male baboons (Papio ursinus). Serial sections from specimens that had been harvested at three, six, and nine months showed that initially the formation of fibrous connective tissue was characterized by a prominent vascular component and by condensations of collagen fibers assembled at the interface of the hydroxyapatite. The morphogenesis of bone was intimately associated with the differentiation of the connective-tissue condensations. Bone formed without an intervening endochondral phase. Although the amount of bone varied considerably, in several specimens extensive bone developed, filling large portions of the porous spaces and culminating in total penetration by bone within the implants. The mean volume fraction composition of the specimens was 20.8 +/- 1.0 per cent (mean and standard error) for bone, 17.3 +/- 1.7 per cent for connective-tissue condensation, 31.9 +/- 1.0 per cent for fibrovascular tissue, 6.4 +/- 0.6 per cent for bone marrow, and 34.6 +/- 0.5 per cent for the hydroxyapatite framework. The amount of bone and marrow increased at each time-period, and the hydroxyapatite framework was significantly reduced between six and nine months. This indicated a moderate biodegradation over time, which was possibly a result of incomplete conversion of carbonate to hydroxyapatite. Linear regression analysis showed a negative correlation between the hydroxyapatite framework and the magnitude of bone formation within the porosities of the hydroxyapatite (p = 0.0001). Biochemical coating of the hydroxyapatite substratum with an allogeneic fibrin-fibronectin protein concentrate prepared from baboon plasma did not significantly increase the amount of bone formation within the porous spaces. The hydroxyapatite substratum may have functioned as a solid-phase domain for anchorage of bone morphogenetic proteins.


Effects of extracts of Salvadora persica on proliferation and viability of human dental pulp stem cells.
Efficacy of an ideal antimicrobial agent depends on its ability to eliminate microorganisms while causing minimal toxicity to host cells. The purpose of this study was to assess the effect of ethanolic and water extracts of Salvadora persica (SP) on proliferation and viability of human dental pulp stem cells (hDPSCs). In this in-vitro study, the effects of seven concentrations of ethanolic and water extracts of SP (ranging from 5.75 mg/ml to 0.08 mg/ml) on hDPSCs were evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. The results were analyzed using one-way ANOVA and Tukey's post-hoc test. P < 0.05 was considered statistically significant. Water extract of SP only had cytotoxic effect at 5.75 mg/ml concentration; and caused significant cell proliferation at 1.43-0.08 mg/ml concentrations at 24 h (P < 0.05). At 48 h, only 0.17 and 0.08 mg/ml concentrations caused significant cell proliferation (P < 0.05). Ethanolic extract of SP at 5.75-1.43 mg/ml concentrations showed severe cytotoxic effects at 24 and 48 h. Other concentrations had no significant effects on cells (P > 0.05). The highest concentrations of both water and ethanolic extracts of SP had cytotoxic effects on hDPSCs. Water extract of SP has favorable effects on cell proliferation at specific concentrations in a time-dependent manner.


Mallory-Weiss syndrome. Characterization of 75 Mallory-weiss lacerations in 528 patients with upper gastrointestinal hemorrhage.
Seventy-five Mallory-Weiss lacerations were visualized endoscopically in 58 of 528 patients evaluated acutely for upper gastrointestinal bleeding. The Mallory-Weiss mucosal laceration is more common than generally recognized, is usually associated with hiatal hernia and a prodrome of retching or vomiting, and the ingestion of alcohol or acetylsalicyclic acid, or both. The lacerations are most commonly gastric and are associated with other mucosal lesions which may in fact be the instigating cause of the retching and vomiting. Although blood loss may be considerable, 90% or more patients with this lesion can be managed nonsurgically with appropriate blood component replacement and occasional use of systemic pitressin. There was one fatality in this series of 58 patients with Mallory-Weiss lacerations.


Influenza Virus Infection Induces ZBP1 Expression and Necroptosis in Mouse Lungs.
Programmed cell death and especially necroptosis, a programmed and regulated form of necrosis, have been recently implicated in the progression and outcomes of influenza in mouse models. Moreover, Z-DNA/RNA binding protein 1 (ZBP1) has been identified as a key signaling molecule for necroptosis induced by Influenza A virus (IAV). Direct evidence of IAV-induced necroptosis has not been shown in infected lungs in vivo. It is also unclear as to what cell types undergo necroptosis during pulmonary IAV infection and whether ZBP1 expression can be regulated by inflammatory mediators. In this study, we found that IAV infection induced ZBP1 expression in mouse lungs. We identified that mediators implicated in the pathogenesis of IAV infection including interferons (IFNs), TNFα, and agonists for Toll-like receptors 3 and 4 were potent inducers of ZBP1 expression in primary murine alveolar epithelial cells, bone marrow derived macrophages, and dendritic cells. We further found that IAV infection induced a strong necroptosis through phosphorylation of the necroptosis effector mixed lineage kinase domain-like protein in infiltrating immune cells and alveolar epithelial cells by day 7 post-infection. Lastly, we found different cell type-specific responses to IAV-induced cell death upon inhibition of caspases and/or necroptosis pathways. Our findings provide direct evidence that IAV infection induces necroptosis in mouse lungs, which may involve local induction of ZBP1 and different programmed cell death signaling mechanisms in alveolar epithelial and infiltrating inflammatory cells in the lungs.


Counterpropagating Radiative Shock Experiments on the Orion Laser.
We present new experiments to study the formation of radiative shocks and the interaction between two counterpropagating radiative shocks. The experiments are performed at the Orion laser facility, which is used to drive shocks in xenon inside large aspect ratio gas cells. The collision between the two shocks and their respective radiative precursors, combined with the formation of inherently three-dimensional shocks, provides a novel platform particularly suited for the benchmarking of numerical codes. The dynamics of the shocks before and after the collision are investigated using point-projection x-ray backlighting while, simultaneously, the electron density in the radiative precursor was measured via optical laser interferometry. Modeling of the experiments using the 2D radiation hydrodynamic codes nym and petra shows very good agreement with the experimental results.


Chemical rescue of mutant proteins in living Saccharomyces cerevisiae cells by naturally occurring small molecules.
Intracellular proteins function in a complex milieu wherein small molecules influence protein folding and act as essential cofactors for enzymatic reactions. Thus protein function depends not only on amino acid sequence but also on the concentrations of such molecules, which are subject to wide variation between organisms, metabolic states, and environmental conditions. We previously found evidence that exogenous guanidine reverses the phenotypes of specific budding yeast septin mutants by binding to a WT septin at the former site of an Arg side chain that was lost during fungal evolution. Here, we used a combination of targeted and unbiased approaches to look for other cases of "chemical rescue" by naturally occurring small molecules. We report in vivo rescue of hundreds of Saccharomyces cerevisiae mutants representing a variety of genes, including likely examples of Arg or Lys side chain replacement by the guanidinium ion. Failed rescue of targeted mutants highlight features required for rescue, as well as key differences between the in vitro and in vivo environments. Some non-Arg mutants rescued by guanidine likely result from "off-target" effects on specific cellular processes in WT cells. Molecules isosteric to guanidine and known to influence protein folding had a range of effects, from essentially none for urea, to rescue of a few mutants by DMSO. Strikingly, the osmolyte trimethylamine-N-oxide rescued ∼20% of the mutants we tested, likely reflecting combinations of direct and indirect effects on mutant protein function. Our findings illustrate the potential of natural small molecules as therapeutic interventions and drivers of evolution.


Rangelands, pastoralists and governments: interlinked systems of people and nature.
We analyse commercially operated rangelands as coupled systems of people and nature. The biophysical components include: (i) the reduction and recovery of potential primary production, reflected as changes in grass production per unit of rainfall; (ii) changes in woody plants dependent on the grazing and fire regimes; and (iii) livestock and wool dynamics influenced by season, condition of the rangeland and numbers of wild and feral animals. The social components include the managers, who vary with regard to a range of cognitive abilities and lifestyle choices, and the regulators who vary in regard to policy goals. We compare agent-based and optimization models of a rangeland system. The agent-based model leads to recognition that policies select for certain management practices by creating a template that governs the trajectories of the behaviour of individuals, learning, and overall system dynamics. Conservative regulations reduce short-term loss in production but also restrict learning. A free-market environment leads to severe degradation but the surviving pastoralists perform well under subsequent variable conditions. The challenge for policy makers is to balance the needs for learning and for preventing excessive degradation. A genetic algorithm model optimizing for net discounted income and based on a population of management solutions (stocking rate, how much to suppress fire, etc.) indicates that robust solutions lead to a loss of about 40% compared with solutions where the sequence of rainfall was known in advance: this is a similar figure to that obtained from the agent-based model. We conclude that, on the basis of Levin's three criteria, rangelands with their livestock and human managers do constitute complex adaptive systems. If this is so, then command-and-control approaches to rangeland policy and management are bound to fail.


Can a smartphone app help manage wounds in primary care?
Although wound care guidelines are available for primary care providers, barriers to assessment and treatment remain. This article examines current evidence supporting wound management, wound guidelines, and provider comfort with wound management in primary care and discusses the need for improved training, education, and the development of a simplified approach to wound management in primary care. This review of evidence examines knowledge of wound care, wound curriculum, and the current availability of guidelines for health care providers at the frontlines. Few primary care curriculums and institutions require wound care education. Access to guidelines, pathways, and educational resources is limited, which negatively effects primary care provider's knowledge and comfort level in treating wounds in current clinical practice. Educating the general practitioner on evidence-based wound management and providing adequate resources remain a priority. Increasing awareness of available electronic wound care applications (apps) can improve a timely wound care assessment, diagnosis, and initiation of treatment.


Radiofrequency global endometrial ablation followed by hysteroscopic sterilization.
To describe the feasibility of performing Essure hysteroscopic sterilization immediately after NovaSure global endometrial ablation (GEA). Descriptive feasibility study (Canadian Task Force classification III). Midwestern United States academic medical center. Twenty-five women (aged 35-49 years) with menorrhagia who elected GEA treatment and requested concurrent permanent sterilization. NovaSure GEA followed immediately by Essure hysteroscopic sterilization. Patients returned 3 months after the procedure for hysterosalpingography (HSG) to document tubal occlusion. The inserts were placed successfully in all 25 patients; 21 returned for 3-month follow-up HSG, as recommended. Bilateral tubal occlusion was documented at 3 months in 19 patients (90%) and unilateral occlusion in 2 patients. Six-month postprocedural HSG in these 2 patients documented bilateral tubal occlusion. Hysterosalpingography was not performed in 4 patients. In all 21 patients with appropriate follow-up, complete occlusion was documented, and the ability to perform or interpret HSG was not affected by endometrial ablation. Essure hysteroscopic sterilization can be safely performed after NovaSure GEA. Intrauterine synechiae do not appear to adversely affect the ability to perform HSG at 3 months or to document tubal occlusion.


Improved Conversation Outcomes After Social Communication Skills Training for People With Traumatic Brain Injury and Their Communication Partners: A Clinical Trial Investigating In-Person and Telehealth Delivery.
Purpose The aim of the study was to investigate the effectiveness of social communication skills training (TBIconneCT) for people with traumatic brain injury (TBI) and their communication partners, delivered in-person or via telehealth, on quality of conversations. Method This study is a clinical trial, including an in-person intervention group (n = 17), a telehealth intervention group (n = 19), and a historical control group (n = 15). Participants were adults at least 6 months post moderate-to-severe TBI with social communication skills deficits and their usual communication partners. Participants completed a casual and purposeful conversation task at pre-intervention, postintervention, and a follow-up assessment. A blinded assessor evaluated conversations using the Adapted Measure of Participation in Conversation and the Adapted Measure of Support in Conversation. Treatment effects were examined by comparing groups on change in ratings between pre- and posttraining. Maintenance of effects was examined using change between posttraining and follow-up assessment. The trial protocol was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615001024538). Results Trained participants with TBI had significant improvements in participation in casual conversation compared to controls. Trained communication partners also had significant improvements compared to controls on ratings of support in casual conversations. However, treatment effects were not maintained at follow-up for two of eight measures. Comparisons between outcomes of in-person and telehealth groups found negligible to small effect sizes for six of eight measures. Conclusions The findings reinforce previous studies demonstrating the efficacy of communication partner training after TBI. Telehealth delivery produced similar outcomes to in-person delivery.


Unique biologic properties of recombinant AAV1 transduction in polarized human airway epithelia.
The choice of adeno-associated virus serotypes for clinical applications is influenced by the animal model and model system used to evaluate various serotypes. In the present study, we sought to compare the biologic properties of rAAV2/1, rAAV2/2, and rAAV2/5 transduction in polarized human airway epithelia using viruses purified by a newly developed common column chromatography method. Results demonstrated that apical transduction of human airway epithelia with rAAV2/1 was 100-fold more efficient than rAAV2/2 and rAAV2/5. This transduction profile in human airway epithelia (rAAV2/1 >> rAAV2/2 = rAAV2/5) was significantly different from that seen following nasal administration of these vectors to mouse lung (rAAV2/5 > rAAV2/1 >> rAAV2/2), emphasizing differences in transduction of these serotypes between these two species. In stark contrast to rAAV2/2 and rAAV2/5, rAAV2/1 transduced both the apical and basolateral membrane of human airway epithelia with similar efficiency. However, the overall level of transduction across serotypes did not correlate with vector internalization. We hypothesized that differences in post-entry processing of these serotypes might influence the efficiency of apical transduction. To this end, we tested the effectiveness of proteasome inhibitors to augment nuclear translocation and gene expression from the three serotypes. Augmentation of rAAV2/1 apical transduction of human polarized airway epithelia was 10-fold lower than that for rAAV2/2 and rAAV2/5. Cellular fractionation studies demonstrated that proteasome inhibitors more significantly enhanced rAAV2/2 and rAAV2/5 translocation to the nucleus than rAAV2/1. These results demonstrate that AAV1 transduction biology in human airway epithelia differs from that of AAV2 and AAV5 by virtue of altered ubiquitin/proteasome sensitivities that influence nuclear translocation.


Time trends in autism diagnosis over 20 years: a UK population-based cohort study.
Autism spectrum disorder is a diagnosis that is increasingly applied; however, previous studies have conflicting findings whether rates of diagnosis rates continue to grow in the UK. This study tested whether the proportion of people receiving a new autism diagnosis has been increasing over a twenty-year period, both overall and by subgroups. Population-based study utilizing the Clinical Practice Research Datalink (CPRD) primary care database, which contains patients registered with practices contributing data to the CPRD between 1998 and 2018 (N = 6,786,212 in 1998 to N = 9,594,598 in 2018). 65,665 patients had a diagnosis of autism recorded in 2018. Time trend of new (incident) cases of autism diagnosis was plotted for all, and stratified by gender, diagnostic subtypes, and developmental stage: infancy and preschool, 0-5 years old; childhood, 6-11 years old; adolescence, 12-19 years old; adults, over 19 years old. There was a 787%, exponential increase in recorded incidence of autism diagnoses between 1998 and 2018; R2 = 0.98, exponentiated coefficient = 1.07, 95% CI [1.06, 1.08], p < .001. The increase in diagnoses was greater for females than males (exponentiated interaction coefficient = 1.02, 95% CI [1.01, 1.03], p < .001) and moderated by age band, with the greatest rises in diagnostic incidence among adults (exponentiated interaction coefficient = 1.06, 95% CI [1.04, 1.07], p < .001). Increases could be due to growth in prevalence or, more likely, increased reporting and application of diagnosis. Rising diagnosis among adults, females and higher functioning individuals suggest augmented recognition underpins these changes.


The mitochondrial translocator protein and arrhythmogenesis in ischemic heart disease.
Mitochondrial dysfunction is a hallmark of multiple cardiovascular disorders, including ischemic heart disease. Although mitochondria are well recognized for their role in energy production and cell death, mechanisms by which they control excitation-contraction coupling, excitability, and arrhythmias are less clear. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is expressed in multiple organ systems. The abundant expression of TSPO in macrophages has been leveraged to image the immune response of the heart to inflammatory processes. More recently, the recognition of TSPO as a regulator of energy-dissipating mitochondrial pathways has extended its utility from a diagnostic marker of inflammation to a therapeutic target influencing diverse pathophysiological processes. Here, we provide an overview of the emerging role of TSPO in ischemic heart disease. We highlight the importance of TSPO in the regenerative process of reactive oxygen species (ROS) induced ROS release through its effects on the inner membrane anion channel (IMAC) and the permeability transition pore (PTP). We discuss evidence implicating TSPO in arrhythmogenesis in the settings of acute ischemia-reperfusion injury and myocardial infarction.


A Novel Combination of ω-3 Fatty Acids and Nano-Curcumin Modulates Interleukin-6 Gene Expression and High Sensitivity C-reactive Protein Serum Levels in Patients with Migraine: A Randomized Clinical Trial Study.
Migraine is a disabling neuroinflammatory condition characterized by increasing the levels of interleukin (IL)-6, a proinflammatory cytokine and C-reactive protein (CRP) which considered as a vascular inflammatory mediator, disrupting the integrity of blood-brain barrier and contributing to neurogenic inflammation, and disease progression. Curcumin and ω-3 fatty acids can exert neuroprotective effects through modulation of IL-6 gene expression and CRP levels. The aim of present study is the evaluation of combined effects of ω-3 fatty acids and nano-curcumin supplementation on IL-6 gene expression and serum level and hs-CRP levels in migraine patients. Eighty episodic migraine patients enrolled in the trial and were divided into four groups as 1) combination of ω-3 fatty acids (2500 mg) plus nano-curcumin (80 mg), 2) ω-3 (2500 mg), 3) nanocurcumin (80 mg), and 4) the control (ω-3 and nano-curcumin placebo included oral paraffin oil) over a two-month period. At the beginning and the end of the study, the expression of IL-6 from peripheral blood mononuclear cells and IL-6 and hs-CRP serum levels were measured, using a real-time PCR and ELISA methods, respectively. The results showed that both of ω-3 and nano-curcumin down-regulated IL-6 mRAN and significantly decreased the serum concentration. hs-CRP serum levels significantly decrease in combination and nano-curcumin within groups (P<0.05). An additive greater reduction of IL-6 and hs-CRP was observed in the combination group suggested a possible synergetic relation. It seems that ω-3 fatty acids and curcumin supplementation can be considered a new promising target in migraine prevention.


Differences in the potential for dementia prevention between major ethnic groups within one country: A cross sectional analysis of population attributable fraction of potentially modifiable risk factors in New Zealand.
Twelve potentially modifiable risk factors (less education, hypertension, obesity, alcohol, traumatic brain injury (TBI), hearing loss, smoking, depression, physical inactivity, social isolation, diabetes, air pollution) account for an estimated 40% of worldwide dementia cases. We aimed to calculate population attributable fractions (PAFs) for dementia for the four largest New Zealand ethnic groups (European, Māori, Asian, and Pacific peoples) to identify whether optimal dementia prevention targets differed by ethnicity. We calculated risk factor prevalence for 10 risk factors using the New Zealand Health Survey 2018/19 and published reports for hearing loss and TBI prevalences. We calculated the PAF for each risk factor using calculated prevalence and relative risk estimates from previous meta-analyses. To account for risk factor overlap, we calculated communality of risk factors and a weighted PAF. The weighted PAF for dementia was 47.7% overall in New Zealand, 47.6% for Europeans, 51.4% for Māori, 50.8% for Pacific peoples, and 40.8% for Asians. Highest PAFs for Europeans were hearing loss (8%) and social isolation (5.7%), and for Asians hearing loss (7.3%) and physical inactivity (5.5%). For Māori and Pacific peoples, highest PAFs were for obesity (7.3% and 8.9% respectively) and hearing loss (6.5% and 6.6%). New Zealand has higher dementia prevention potential than worldwide estimates with high prevalences of untreated hearing loss and obesity. The relative contribution of individual risk factors PAFs varies by ethnic group. Public health strategies for dementia prevention need to be tailored to these differences. Health Research Council of New Zealand (HRC:20/021).


Scholar in the SEPR spotlight: Ian Douglas.
In this reflective essay of intellectual autobiography, I respond to a series of questions the journal editor Wei-Ning Xiang asked about my 55-year journey from applied geography to socio-ecological practice research. These are (1) what and/or who had inspired your career most in geography and socio-ecological practice research? (2) Throughout your 55-year academic journey, did you ever reorient your ambitions in scholarly pursuit, or even reinvent yourself in your academic life? What motivated you in each of these instances? (3) How do you measure success in your work? Among many accomplishments, what are the top three that you are most proud of? (4) From your personal experience, what would be the most important attributes for a well-lived, fully realised, and meaningful life? Do you have any tips for maintaining work-life balance? (5) Do you have any specific advice for younger scholars in geography and socio-ecological practice research? (6) What are the three most interesting images reflecting turning points in your career? I hope that my experiences and insights showcased in this essay are helpful to the younger generations of geographers and socio-ecological practice researchers.


Increasing appearance of reassortant influenza B virus in Taiwan from 2002 to 2005.
Genetic and antigenic analyses of influenza B virus field strains isolated in Taiwan from 1998 to 2005 were performed. To investigate the molecular evolution of influenza B viruses, sequence analysis of the hemagglutinin (HA1 subunit) and neuraminidase genes was performed. All influenza B viruses isolated between 1998 and 2000 belonged to the B/Yamagata/16/88 lineage. The B/Victoria/2/87 lineage, which was cocirculating with the Yamagata lineage, was identified in Taiwan in March 2001. Concurrently, there was an increasing prevalence of this lineage in many parts of the world, including North America and Europe, during the 2001-2002 season. Since 2002, genetic reassortants of influenza B virus with the Victoria lineage of hemagglutinin and the Yamagata lineage of neuraminidase have been found at a rate of 46%. Therefore, in 2002, at least three sublineages of influenza B virus strains, the B/Shanghai/361/2002-like strain (Yamagata lineage), the B/Hong Kong/330/01-like strain (Victoria lineage), and the B/Hong Kong/1351/02-like strain (B reassortant lineage), were identified in Taiwan. The results showed that genetically distinct lineages can cocirculate in the population and that the reassortment among these strains plays a role in generating the genetic diversity of influenza B viruses. Interestingly, from January to April 2005, B reassortant viruses became dominant (73%) in Taiwan, which indicated that a mismatch had occurred between the influenza B vaccine strain recommended for the 2004-2005 season in the Northern hemisphere by the World Health Organization and the epidemic strain.


Rethinking cortical recycling in ventral temporal cortex.
High-level visual areas in ventral temporal cortex (VTC) support recognition of important categories, such as faces and words. Word-selective regions are left lateralized and emerge at the onset of reading instruction. Face-selective regions are right lateralized and have been documented in infancy. Prevailing theories suggest that face-selective regions become right lateralized due to competition with word-selective regions in the left hemisphere. However, recent longitudinal studies examining face- and word-selective responses in childhood do not provide support for this theory. Instead, there is evidence that word representations recycle cortex previously involved in processing other stimuli, such as limbs. These findings call for more longitudinal investigations of cortical recycling and a new era of work that links visual experience and behavior with neural responses.


1999 Nova Award winners.
No hospital creates a healthier community all by itself. But it can give its neighbors a jump start. As the winners of this year's NOVA Awards show, the result is a better life for the most vulnerable--the sickest, the poorest, the youngest, the oldest. And by tackling problems beyond their traditional turf, NOVA winners earn raves for leadership.


Behavioral effects of 0 and 0.05% blood alcohol in male volunteers.
Five behavioral tests were evaluated to determine their sensitivity to the subtle central nervous system (CNS) depressant effects produced by ingestion of ethanol. Twenty-one adult male volunteers received 0 and 1.4 ml 100 proof vodka/kg body weight according to a "double-blind" crossover design. Behavioral tests were conducted between 15 and 65 minutes after ethanol ingestion, when blood alcohol concentrations (BAC's) were between 0.05 and 0.06%. Tests evaluated were Archimedes spiral, digit span memory, critical flicker fusion, stabilometry and tachistoscope. Multivariate analysis of variance (MANOVA) using composite scores representing the individual tests indicated that the battery as a whole was sensitive to ethanol effects. Repeated measures analysis of variance (ANOVA) on each test indicated that critical flicker fusion, stabilometry and tachistoscope contributed more to the overall sensitivity of the battery than did digit span memory and Archimedes spiral.


The Physics of ultrafast saturable absorption in graphene.
The ultrafast saturable absorption in graphene is experimentally and theoretically investigated in the femtosecond (fs) time regime. This phenomenon is well-modeled with valence band depletion, conduction band filling and ultrafast intraband carrier thermalization. The latter is dominated by intraband carrier-carrier scattering with a scattering time of 8 ( +/- 3) fs, which is far beyond the time resolution of other ultrafast techniques with hundred fs laser pulses. Our results strongly suggest that graphene is an excellent atomic layer saturable absorber.


Development of liposome encapsulated clindamycin for treatment of acne vulgaris.
The enhancement of topical delivery of hydrophilic substances by use of multilammelar liposomes was measured ex vivo on pig ear skin and in vivo on hairless mice by electron paramagnetic resonance method (EPR). Multilamellar liposomes with different lipid composition (final concentration of membrane components is 48 mg/ml) were loaded with a hydrophilic spin probe GluSL, which does not penetrate the liposome membrane easily. They were characterized with respect to their stability, entrapped volume and enhancement characteristics. We observed significant differences in the properties of different types of liposomes with respect to their stability when in contact with the skin and their penetration into the skin. The results measured in vivo are consistent with those obtained ex vivo. On the basis of these findings the liposomes with appropriate stability and intradermal penetration characteristics were chosen for the development of liposome-encapsulated 1% clindamycin preparation for therapy of acne vulgaris. A double-blind clinical study was conducted to assess the safety and efficiency of liposome-encapsulated 1% clindamycin solution versus 1% clindamycin solution (Klimicin T, Lek). On the basis of the clinical trial it may be concluded that liposome-encapsulated 1% clindamycin solution was therapeutically superior over conventional 1% clindamycin solution in the treatment of acne vulgaris.


Polar body analysis by array comparative genomic hybridization accurately predicts aneuploidies of maternal meiotic origin in cleavage stage embryos of women of advanced maternal age.
How accurate is array comparative genomic hybridization (array CGH) analysis of the first polar body (PB1) and second polar body (PB2) in predicting aneuploidies of maternal meiotic origin in the cleavage stage embryos of women of advanced maternal age? Almost all of the aneuploidies detected in cleavage stage embryos were associated with copy number changes in the polar bodies (93%) and all but one (98.5%) were predicted to be aneuploid. A minority of copy number changes (17%), mainly in PB1, did not result in the predicted changes in the embryo, but many of these were small copy number changes, which are likely to be artefacts. Chromosome aneuploidy is a major cause of pregnancy failure and loss, abnormal pregnancy and live births. Most aneuploidy is of maternal meiotic origin and increases exponentially in the decade preceding the menopause. A pilot study demonstrated a high rate of concordance between the chromosomal status predicted by polar body analysis and the corresponding zygotes in women of advanced maternal age. Polar body biopsy and array CGH analysis of mature oocytes, which fertilized normally, to identify segregation errors in meiosis, followed by the analysis of the corresponding cleavage stage embryos (n = 34), in a consecutive series of stimulated and natural IVF cycles in women of advanced maternal age. Twenty couples requesting aneuploidy screening (mean ± SD of maternal age 39 ± 3 years) had 16 controlled ovarian hyperstimulation and 7 natural IVF cycles. PB1 and PB2 were biopsied from mature oocytes, prior to intracytoplasmic sperm injection (ICSI) and following confirmation of normal fertilization, respectively. Array CGH was used to detect chromosome copy number changes and to predict aneuploidy in the corresponding embryos. Embryos with normal copy number in both polar bodies were transferred but, 34 cleavage stage embryos, most of which were predicted to have one or more aneuploidies of maternal meiotic origin, were analysed in whole after removal of the zona by array CGH, on Day 3 post-ICSI. Thirty cleavage stage embryos, predicted to have one or more aneuploidies, were all confirmed to be aneuploid (100% concordant). Seventy four aneuploidies were detected in these embryos. Sixty-nine (93%) aneuploidies were associated with copy number changes in the polar bodies and 68 (98.5%) of these had been predicted to be aneuploid. Also, 19 of 20 (95%) balanced combinations of chromatid gain/loss in PB1/PB2 accurately predicted normal copy number in the corresponding embryos. However, 17 (12%) copy number changes in the polar bodies did not result in the expected outcome, including 12 false positive predictions of aneuploidy. Most of these involved copy number changes that were smaller than would be expected for whole chromosome or chromatid imbalance and occurred significantly more often in PB1 than PB2 (P < 0.0005). Three other embryos with only small copy number changes and one embryo with a partial chromosome loss in PB2, were all confirmed to be euploid. Accurate false positive and negative rates will require follow-up of both euploid and aneuploid embryos, ideally using molecular genetic markers to detect aneuploidy independently and to identify their origin. Polar body biopsy and array CGH analysis is efficient and accurately predicts most aneuploidies in cleavage stage embryos. However, the size of the ratio shifts, particularly in PB1, should always be compared with the X chromosome shift before it can be concluded that there is a real copy number change. Study funded by Embryogenesis, Athens. P.S. and A.H.H. are employed full time and part time, respectively, by BlueGnome Ltd, Cambridge, UK.


Multiple descent cost competition: restorable self-organization and multimedia information processing.
Multiple descent cost competition is a composition of learning phases for minimizing a given measure of total performance, i.e., cost. If these phases are heterogeneous toward each other, the total learning algorithm shows a variety of extraordinary abilities; especially in regards to multimedia information processing. In the first phase of descent cost learning, elements of source data are grouped. Simultaneously, a weight vector for minimal learning, (i.e., a winner), is found. Then, the winner and its partners are updated for further cost reduction. Therefore, two classes of self-organizing feature maps are generated. One is called a grouping feature map, which partitions the source data. The other is an ordinary weight vector feature map. The grouping feature map, together with the winners, retains most of the source data information. This feature map is able to assist in a high quality approximation of the original data. Traditional weight vector feature maps lack this ability. Another important capacity of the grouping feature map is that it can change its shape. Thus, the grouping pattern can accept external directions in order to metamorphose. In the text, the total algorithm of the multiple descent cost competition is explained first. In that section, image processing concepts are introduced in order to assist in the description of this algorithm. Then, a still image is first data-compressed (DC). Next, a restored image is morphed using the grouping feature map by receiving directions given by an external intelligence. Next, an interpolation of frames is applied in order to complete animation coding (AC). Thus, multiple descent cost competition bridges "DC to AC." Examples of multimedia processing on virtual digital movies are given.


Changes to DA-CPR instructions: can we reduce time to first compression and improve quality of bystander CPR?
Dispatcher-assisted CPR (DA-CPR) can increase rates of bystander CPR, survival, and quality of life following cardiac arrest. Dispatcher protocols designed to improve rapid recognition of arrest and coach CPR may increase survival by (1) reducing preventable time delays to start of chest compressions and (2) improving the quality of bystander CPR. We conducted a randomized controlled trial comparing a simplified DA CPR script to a conventional DA CPR script in a manikin cardiac arrest simulation with lay participants. The primary outcomes measured were the time interval from call receipt to the first chest compression and the core metrics of chest compression (depth, rate, release, and compression fraction). CPR was measured using a recording manikin for the first 3 min of participant CPR. Of the 75 participants, 39 were randomized to the simplified instructions and 36 were randomized to the conventional instructions. The interval from call receipt to first compression was 99 s using the simplified script and 124 s using the conventional script for a difference of 24s (p<0.01). Although hand position was judged to be correct more often in the conventional instruction group (88% versus 63%, p<0.01), compression depth was an average 7 mm deeper among those receiving the simplified CPR script (32 mm versus 25 mm, p<0.05). No statistically significant differences were detected between the two instruction groups for compression rate, complete release, number of hands-off periods, or compression fraction. Simplified DA-CPR instructions to lay callers in simulated cardiac arrest settings resulted in significant reductions in time to first compression and improvements in compression depth. These results suggest an important opportunity to improve DA CPR instructions to reduce delays and improve CPR quality.


Use of nucleic acids anchor system to reveal apoferritin modification by cadmium telluride nanoparticles.
The aim of this study was to synthesize cadmium telluride nanoparticles (CdTe NPs) modified apoferritin, and examine if apoferritin is able to accommodate CdTe NPs. Primarily, the thermostability of horse spleen apoferritin was tested and it's unfolding at 70 °C was observed. Cadmium telluride nanoparticles (CdTe NPs) were synthesized both within apoferritin protein cage and on its surface. The thermal treatment of apoferritin with CdTe NPs resulted in the aggregation of cores, which was indicated by changes in the absorption spectra and the shape of apoferritin tryptophan fluorescence. The apoferritin modified with CdTe NPs was additionally modified with gold nanoparticles and attached to magnetic particles via oligonucleotide using gold affinity to thiol group. This anchor system was used to separate the construct using external magnetic field and to analyse the molecules attached to apoferritin.


Are we faced with two human species?
Problems could be found in the fact that we very often look for one deciding, definitive reason for the process of aging. It is a sort of search for a big discovery, like a fountain of youth or such. More and more authors are trying to explain the unknowns in the understanding of these observations about aging by adding the statement that there are two subgroups in the general population. This acknowledgment of two subpopulations explains why there are numerous cases that cannot be explained, defined, or fitted in basic observations about caloric restrictions and the delay of reproduction. The identification of those two groups would allow us to find more realistic results in studies and therefore a more efficient therapy of certain diseases. This hypothesis does not contradict theories of aging that we have accepted (at least not the majority of accepted theories), and this hypothesis also does not contradict the fact that there is a large interindividual variability. This hypothesis doubts, and claims there are exceptions to, the starting assumption of geriatrics and gerontology that: "parallel to the aging process the functions of all organs and organ systems lessen."


In vitro static digestion reveals how plant proteins modulate model infant formula digestibility.
Infant formulas (IFs) are the key nutritional source for infants who cannot be breastfed. There is currently a growing interest in these sensitive products in order to control their quality and to design their composition with regard to nutritional balance. In a context of sustainable development and increasing growth of the world population, it seems essential to search for alternative to animal protein in food today. Plant proteins offer interesting nutritional and functional benefits thanks to the latest improvement through research and development. In this context, five model IFs were developed with identical composition, except that 50% of the proteins were either whey proteins in the "milk-reference IF", pea, faba bean, rice or potato proteins in the four "plant IFs" tested. The IFs were evaluated using an in vitro static gastro-intestinal model simulating infant conditions. The protein hydrolysis degree (DH) and the amino acid bioaccessibility (AAB) were used as indicators of protein digestibility. Results showed that both DH and AAB were very similar between the milk-reference IF, pea and faba bean IFs, but significantly lower for the rice and potato IFs. This study provides new insights into the impact of protein sources on IF digestibility.


A review of cross-sectional imaging, ultrasound and nuclear medicine utilization patterns in paediatric patients in Ireland, 2003-12.
Recent trends in paediatric imaging have been examined in Australia and the USA. Such literature in Europe is sparse, incomprehensive and outdated. This research investigated (1) population-based trends in the use of advanced medical imaging in children in Ireland from 2003 to 2012; (2) its use across age and gender; and (3) the most commonly performed examinations within each modality. A retrospective cohort analysis study was carried out within Irish paediatric hospitals. All CT, MRI, ultrasound and nuclear medicine (NM) annual examination data from 2003 to 2012 was obtained from radiology information systems. 224,173 imaging procedures were carried out on 84,511 patients, 68% of which were ultrasound, 15% were MRI, 11% were CT and 6% were NM. Between 2003 and 2012, MRI (+280%) and CT (+80%) saw the largest increases in use, followed by ultrasound (+67%) and NM (+10%). Almost half of the study population were less than 3 years old. CT imaging was more frequent than MR in 2005. By 2012, MR rates were twice that of CT. CT imaging rates were the lowest in the youngest age categories. Advanced imaging use, particularly MRI, has risen substantially over the past 10 years. The utilization of non-ionizing modalities increased between 2003 and 2012, especially in brain, spinal and abdominal imaging. MR is now used at twice the frequency of CT. Longitudinal advanced imaging utilization trends, including CT trends, have been established in the Irish paediatric population.


Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA.
Pseudomonas aeruginosa is an opportunistic ESKAPE pathogen that produces two lectins, LecA and LecB, as part of its large arsenal of virulence factors. Both carbohydrate-binding proteins are central to the initial and later persistent infection processes, i. e. bacterial adhesion and biofilm formation. The biofilm matrix is a major resistance determinant and protects the bacteria against external threats such as the host immune system or antibiotic treatment. Therefore, the development of drugs against the P. aeruginosa biofilm is of particular interest to restore efficacy of antimicrobials. Carbohydrate-based inhibitors for LecA and LecB were previously shown to efficiently reduce biofilm formations. Here, we report a new approach for inhibiting LecA with synthetic molecules bridging the established carbohydrate-binding site and a central cavity located between two LecA protomers of the lectin tetramer. Inspired by in silico design, we synthesized various galactosidic LecA inhibitors with aromatic moieties targeting this central pocket. These compounds reached low micromolar affinities, validated in different biophysical assays. Finally, X-ray diffraction analysis revealed the interactions of this compound class with LecA. This new mode of action paves the way to a novel route towards inhibition of P. aeruginosa biofilms.


Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD).
A number of studies have demonstrated that the common polymorphism 677C-->T in the gene encoding 5, 10-methylenetetrahydrofolate reductase (MTHFR) leads to a thermolabile variant with decreased enzyme activity and to mildly elevated plasma homocysteine. 677TT homozygosity was shown to be more frequent in NTD probands compared with controls in some studies. Recently, another polymorphism, 1298A-->C, in the MTHFR gene was described and combined heterozygosity 677CT/1298AC was suggested to be an additional risk factor for NTD. The present study examines the genotype and haplotype distribution of the two polymorphisms in the German population and evaluates the impact on NTD individuals and their relatives. To determine the haplotype of all individuals tested, we developed an easy-to-perform ARMS-RFLP test. Our data show that the two polymorphisms are in linkage disequilibrium in the general population and in NTD individuals. There was no statistically significant difference in allele and genotype frequency between probands (patients, fetuses) and controls (P > 0.10) and between observed and expected values for mother-child pairs (P > 0.80). Taking into account gender, an increased rate of 677CT heterozygotes was found in affected and unaffected males compared to affected and unaffected females. A family-based association study using a multiallelic transmission disequilibrium test (TDT) also shows that transmission rates do not deviate significantly from equilibrium (P > 0.50). Thus, our data provide no evidence for an association between NTD phenotype and MTHFR 677C/T-1298A/C genotypes and haplotypes.


Formyl Peptide Receptor 1 Signaling in Acute Inflammation and Neural Differentiation Induced by Traumatic Brain Injury.
Traumatic brain injury (TBI) is a shocking disease frequently followed by behavioral disabilities, including risk of cerebral atrophy and dementia. N-formylpeptide receptor 1 (FPR1) is expressed in cells and neurons in the central nervous system. It is involved in inflammatory processes and during the differentiation process in the neural stem cells. We investigate the effect of the absence of Fpr1 gene expression in mice subjected to TBI from the early stage of acute inflammation to neurogenesis and systematic behavioral testing four weeks after injury. C57BL/6 animals and Fpr1 KO mice were subjected to TBI and sacrificed 24 h or four weeks after injury. Twenty-four hours after injury, TBI Fpr1 KO mice showed reduced histological impairment, tissue damage and acute inflammation (MAPK activation, NF-κB signaling induction, NRLP3 inflammasome pathway activation and oxidative stress increase). Conversely, four weeks after TBI, the Fpr1 KO mice showed reduced survival of the proliferated cells in the Dentate Gyrus compared to the WT group. Behavioral analysis confirmed this trend. Moreover, TBI Fpr1 KO animals displayed reduced neural differentiation (evaluated by beta-III tubulin expression) and upregulation of astrocyte differentiation (evaluated by GFAP expression). Collectively, our study reports that, immediately after TBI, Fpr1 increased acute inflammation, while after four weeks, Fpr1 promoted neurogenesis.


Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice.
Despite the progress in the treatment of lysosomal storage disorders (LSDs) mainly by enzyme replacement therapy, only limited success was reported in targeting the appropriate lysosomal enzyme into the brain. This prevents efficient clearance of neuronal storage, which is present in many of these disorders including alpha-mannosidosis. Here we show that the neuropathology of a mouse model for alpha-mannosidosis can be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of different doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a significant clearance (<70%) in visceral tissues, higher doses were needed for a clear effect in central and peripheral nervous tissues. A distinct reduction (<50%) of brain storage required repeated high-dose injections (500 U/kg), whereas lower doses (250 U/kg) were sufficient for clearance of stored substrates in peripheral neurons of the trigeminal ganglion. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to a nearly complete disappearance of storage vacuoles. Importantly, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seems to be independent of mannose-6-phosphate receptors, which is consistent with the low phosphorylation profile of the enzyme. These data suggest that high-dose injections of low phosphorylated enzymes might be an interesting option to efficiently treat LSDs with CNS involvement.


Guilty pleas of youths and adults: Differences in legal knowledge and decision making.
Few studies have examined differences in the guilty plea decisions of youth and adults. In interviews with 64 youth (X = 15.9, SD = 1.2) and 56 adults (X = 38.5, SD = 11.5) who pleaded guilty to felonies in New York City, we found important differences between the youths and adults in their understanding of the plea process, the factors they considered when making decisions, and their rationales for their decisions. Youth were less likely to recognize that a guilty plea resulted in a criminal record and to understand the trial process, and they reported having considered fewer potential outcomes in their decision making than adults. Like adults, youth overwhelmingly reported pleading guilty for reduced charges or penalties, but were substantially less likely than adults to understand the nature of the rights they were waiving. Our findings raise the question of whether the assumption of competence for youth is reasonable, and whether steps to assess youth understanding and decisional competence should be taken before youth are allowed to enter into plea agreements. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Prevalence of symptoms and associated comorbidities of testosterone deficiency syndrome in the Korean general population.
Testosterone deficiency syndrome (TDS) is a prevalent disease of the aging male with much confusion to its associated presentation, diagnosis, and comorbidities. We investigated the overall prevalence of TDS and its putative symptoms and associated diseases in a nationwide study on participants recruited from routine checkup. One thousand eight hundred seventy-five participants seeking biennial health checkup were enrolled from a nationwide distribution of randomly selected registry of primary clinics. Putative symptoms and comorbidities were assessed for serum testosterone-dependent prevalence change, independent of age. The identified symptoms were then assessed by multivariate backward stepwise binominal regression to determine the optimal reference level of testosterone and the strength of the associated comorbidities. TDS was assessed by serum testosterone, the Aging Males' Symptom scale, and the Androgen Deficiency in Aging Male questionnaire. Patient body habitus measurements and history of associated comorbidities were also described. The dependent variables included the age-specific prevalence of decreased testosterone and the probability of TDS-specific symptoms. Grossly 10.2% of the participants fell into the criteria for TDS. Testosterone was highly age dependent, and most putative symptoms of TDS showed significant age dependence but was not affected by serum testosterone levels. However, the symptoms of decreased libido and erectile dysfunction, and comorbidities such as hypertension, type 2 diabetes, and obesity showed relevant dependence on serum testosterone levels as well as age above 50 years of age. Furthermore, these symptoms were also affected at different serum testosterone thresholds. Decreased libido increased significantly at serum testosterone levels of 550 ng/dL (odds ratio [OR] = 1.295, 95% confidence interval [CI] = 1.047-1.601), and erectile dysfunction was affected by serum testosterone levels at 250 ng/dL (OR = 1.369, 95% CI = 1.005-1.866). Most symptoms and diseases thought to be associated with TDS are primarily age dependent. Few sexual symptoms and diseases such as hypertension, diabetes, and obesity show testosterone dependence only at older ages.


Function and disability status among women with fistula using WHODAS2.0: A descriptive study from Rwanda and Democratic Republic of Congo.
To assess function and disability among women in Rwanda and Democratic Republic of Congo living with fistula and identify characteristics associated with higher disability scores. Women presenting for fistula care were recruited. Eligible participants underwent a physical examination to classify fistula type and completed the WHO Disability Assessment Schedule 2.0 questionnaire to ascertain the impact of fistula on function across six domains: cognition, mobility, self-care, getting along, life activities, and participation. Disability scores were calculated (where 0 = no disability and 100 = complete disability). Participants were grouped according to no, low, or high disability status; results were examined to determine the domains most affected. Among 69 participants, fistula type included: vesicovaginal (59.4%), ureterovaginal (14.5%), total absence of proximal urethra (11.6%), and rectovaginal (14.5%). Median disability score was 43.0/100 (interquartile range 26.0-67.0); 83% exhibited high disability status. Life activities and participation in society domains were most affected. Women with rectovaginal fistula reported the lowest scores, and those with total absence of proximal urethra reported the highest scores. WHO Disability Assessment Schedule 2.0 represents a simple, robust measure of global disability status, aligns with research efforts to estimate maternal disability, and may inform health needs and resource allocation for this population. In this study, disability was common, varied by fistula type, and affected physical, mental, and social domains.


There is currently a growing demand in favor of non-conventional medicines. The use of unconventional practices is interesting, not only for the patient himself, but also for the community (in order to face the contemporary problems of health expenditure, access to healthcare, and the aging of the population). However, we can ask ourselves about the protection of patient's rights when he uses unconventional care practices. There is a gap between the growing demand for unconventional care, and the low level of legal framework of these practices by French law. The near absence of supervision of certain diplomas and the exercise of certain professions raises the question of the safety and quality of the care provided. Other uncertainties appear regarding the respect of the patient's personal rights (information, consent, refusal of treatment, secrecy of health information, etc.). The current legal framework deserves to be developed to ensure a better protection for patients who use unconventional care.


Primary structure of the tolC gene that codes for an outer membrane protein of Escherichia coli K12.
We present the nucleotide sequence of the tolC gene of Escherichia coli K12, and the amino acid sequence of the TolC protein (an outer membrane protein) as deduced from it. The mature TolC protein comprises 467 amino acid residues, and, as previously reported (1), a signal sequence of 22 amino acid residues is attached to the N-terminus. The C-terminus of the gene is followed by a stem-loop structure (8 base pair stem, 4 base loop) which may be a rho-independent termination signal. The codon usage of the gene is nonrandom; the major isoaccepting species of tRNA are preferentially utilised, or, among synonomous codons recognized by the same tRNA, those codons are used which can interact better with the anticodon (2,3). In contrast to the codon usage for other outer membrane proteins of E. coli (4) the rare arginine codons AGA and AGG are used once and twice respectively.


CcpA Affects Infectivity of Staphylococcus aureus in a Hyperglycemic Environment.
Many bacteria regulate the expression of virulence factors via carbon catabolite responsive elements. In Gram-positive bacteria, the predominant mediator of carbon catabolite repression is the catabolite control protein A (CcpA). Hyperglycemia is a widespread disorder that predisposes individuals to an array of symptoms and an increased risk of infections. In hyperglycemic individuals, the bacterium Staphylococcus aureus causes serious, life-threatening infections. The importance of CcpA in regulating carbon catabolite repression in S. aureus suggests it may be important for infections in hyperglycemic individuals. To test this suggestion, hyperglycemic non-obese diabetic (NOD; blood glucose level ≥20 mM) mice were challenged with the mouse pathogenic S. aureus strain Newman and the isogenic ccpA deletion mutant (MST14), and the effects on infectivity were determined. Diabetic NOD mice challenged with the ccpA deletion mutant enhanced the symptoms of infection in an acute murine pneumonia model relative to the parental strain. Interestingly, when diabetic NOD mice were used in footpad or catheter infection models, infectivity of the ccpA mutant decreased relative to the parental strain. These differences greatly diminished when normoglycemic NOD mice (blood glucose level ≤ 10 mM) were used. These data suggest that CcpA is important for infectivity of S. aureus in hyperglycemic individuals.


Contaminants in surface water and sediments near the Tynagh silver mine site, County Galway, Ireland.
A former silver mine in Tynagh, Co. Galway, Ireland is one of the most contaminated mine sites in Europe with maximum concentrations of Zn, As, Pb, Mn, Ni, Cu, and Cd far exceeding guideline values for water and sediment. The aims of this research were to 1) further assess the contamination, particularly metals, in surface water and sediment around the site, and 2) determine if the contamination has increased 10 years after the Environmental Protection Agency Ireland (EPAI) identified off-site contamination. Site pH is alkaline to neutral because CaCO3-rich sediment and rock material buffer the exposed acid generating sulphide-rich ore. When this study was compared to the previous EPAI study conducted 10 years earlier, it appeared that further weathering of exposed surface sediment had increased concentrations of As and other potentially toxic elements. Water samples from the tailings ponds and adjacent Barnacullia Stream had concentrations of Al, Cd, Mn, Zn and Pb above guideline values. Lead and Zn concentrations from the tailings pond sediment were 16 and 5 times higher, respectively, than concentrations reported 10 years earlier. Pb and Zn levels in most sediment samples exceeded the Expert Group (EGS) guidelines of 1000 and 5000 mg/kg, respectively. Arsenic concentrations were as high as 6238 mg/kg in the tailings ponds sediment, which is 62 and 862 times greater than the EGS and Canadian Soil Quality Guidelines (CSQG), respectively. Cadmium, Cu, Fe, Mn, Pb and Zn concentrations in water and sediment were above guideline values downstream of the site. Additionally, Fe, Mn and organic matter (OM) were strongly correlated and correlated to Zn, Pb, As, Cd, Cu and Ni in stream sediment. Therefore, the nearby Barnacullia Stream is also a significant pathway for contaminant transport to downstream areas. Further rehabilitation of the site may decrease the contamination around the area.


Periodic meningitis and familial Mediterranean fever.
A 33-year-old man had had, since he was 20 years old, recurrent attacks of fever, rash, and aseptic lymphocytic meningitis. A nephrotic syndrome developed that was found, on renal biopsy, to be due to amyloid deposit. After colchicine therapy, no further recurrence of fever and meningitis was observed. These findings suggest that aseptic periodic meningitis (Mollaret's syndrome) should be considered as an unusual manifestation of familial Mediterranean fever.


[Nephrotoxicity of cefpirome sulfate in rabbits--single and multiple intravenous administration].
Nephrotoxic potential of cefpirome sulfate (CPR) was examined by single and multiple intravenous administrations to Japanese white male rabbits. In single administration studies, no nephrotoxic symptoms were observed at the dose level of 320 mg/kg of CPR or less. At the dose level of 500 mg/kg or more, nephrotoxic findings were noted in both CPR and cefazolin sodium(CEZ) groups, such as proteinuria, glucosuria, increase in serum level of urea nitrogen, creatinine and uric acid, and necrosis and calcification in the proximal tubular epithelium of kidney. Renal phenolsulfonphthalein(PSP) excretion was suppressed at the dose level of 500 mg/kg of CPR or more, and 2000 mg/kg of CEZ. In 14 and 21 days repeated administration studies, no nephrotoxic symptoms were observed at the dose level of 100 mg/kg of CPR and CEZ or less. At the dose level of 200 mg/kg of CPR or more, urinary and serum biochemical findings mentioned above were observed, and histopathological changes in the kidney described above were added in 400 mg/kg group. The similar nephrotoxic symptoms including histopathological changes of the kidney were observed in the groups of 100 mg/kg of cefaloridine(CER) and 200 mg/kg of CEZ. In addition, renal PSP excretion was suppressed in the group of 200 mg/kg of CEZ. The results would suggest that CPR is less nephrotoxic than CER and that the nephrotoxic potential of CPR is comparable to CEZ because CPR caused more severe renal failures in single administration study and less severe renal failures in multiple administration study than CEZ.


Graft Rejection Prediction Following Kidney Transplantation Using Machine Learning Techniques: A Systematic Review and Meta-Analysis.
Kidney transplantation is recommended for patients with End-Stage Renal Disease (ESRD). However, complications, such as graft rejection are hard to predict due to donor and recipient variability. This study discusses the role of machine learning (ML) in predicting graft rejection following kidney transplantation, by reviewing the available related literature. PubMed, DBLP, and Scopus databases were searched to identify studies that utilized ML methods, in predicting outcome following kidney transplants. Fourteen studies were included. This study reviewed the deployment of ML in 109,317 kidney transplant patients from 14 studies. We extracted five different ML algorithms from reviewed studies. Decision Tree (DT) algorithms revealed slightly higher performance with overall mean Area Under the Curve (AUC) for DT (79.5% ± 0.06) was higher than Artificial Neural Network (ANN) (78.2% ± 0.08). For predicting graft rejection, ANN and DT were at the top among ML models that had higher accuracy and AUC.


Ultrasonography for Preoperative Diagnosis of Retroperitoneal Fibrosis.
This study aimed to assess the application of ultrasonography for preoperative diagnosis of retroperitoneal fibrosis (RPF). A total of 51 patients with clinically suspected RPF underwent transabdominal ultrasonography and ultrasound-guided histopathologic biopsy (tAU-UGHB). Retroperitoneal fibrosis was diagnosed in 35 patients; of these, 31 cases (88.6%) received a diagnosis using tAU-UGHB. The ultrasonographic images mainly showed solid, irregular isoechoic masses, which were present behind the retroperitoneum and surrounded the abdominal aorta, inferior vena cava, and ureters and had clear borders with the encapsulated structures. Compared with other retroperitoneal lesions, RPF lesions were mainly located below the initial level of the renal artery, and their internal flow signals were not rich (P < 0.05). Retroperitoneal fibrosis had characteristic ultrasonographic features, and color Doppler ultrasound-guided biopsy could be positioned accurately, safely, and efficiently; therefore, tAU-UGHB can be used as an effective modality for preoperative diagnosis of RPF.


Investigating conspecific CsRV1 transmission in Callinectes sapidus.
A reo-like virus, CsRV1, is found in blue crabs, Callinectes sapidus, from every North American location assessed, including Chesapeake Bay and the Atlantic and Gulf coasts, USA and associated with blue crabs in softshell production. CsRV1-associated crab mortality is prevalent in captive crabs, but it is still unknown how CsRV1 is transmitted. The purpose of this study was to examine the role that conspecific predation or scavenging may play in per os transmission in single exposure and repeated exposure experiments. For viruses without cell culture propagation, repeated exposure experiments have the challenge of presenting the virus consistently during the experiment and across time replicates. In a single-exposure experiment, none of the crabs fed muscle tissue of crabs carrying intense infections of CsRV1 developed CsRV1 infections. In a repeated-exposure trial, using infected muscle tissue prepared in alginate blocks, CsRV1 was detected in 11% of the crabs fed infected tissue but was not significantly different from the control group fed alginate lacking CsRV1. For repeated per os exposure experiments, the study demonstrated the utility of using alginate to present the same homogenous sample of virus, both injected and per os, over time for oral challenge experiments. Conspecific predation and scavenging could be a transmission route, but future work into this and other possible routes of transmission for CsRV1 is important to better understand the role this virus plays in wild crab populations and the soft-shell crab industry.


Interaction between postpartum stage and litter age on maternal caregiving and medial preoptic area orexin.
Most maternal caregiving behaviors change across lactation to match the developmental needs of the continuously aging offspring. However, it is mostly unknown whether the dams' postpartum stage or litter age is the primary driving force of these changes. In this study, postnatal day 1 and 8 litters were cross-fostered or in-fostered to postpartum day 1 or 8 dams. Five days later, undisturbed observations of maternal caregiving behaviors were performed on the subsequent two days. We found a main effect of dams' postpartum stage on the frequency that mothers spent with the pups and displayed erect postures over them (hovering over and kyphosis), although it was mostly driven by an interaction between postpartum stage and litter age: early-postpartum dams were in contact with younger litters and in erect postures more often with younger litters compared to later-postpartum dams with younger litters. Additionally, there was an interaction between postpartum stage and litter age on the litter weights because older litters living with later-postpartum dams were heavier than older litters living with early-postpartum dams. There was also an interaction between postpartum stage and litter age on the dams' bodyweight, with early-postpartum dams living with younger litters weighing the least and later-postpartum dams living with younger litters weighing the most. Because activity of the neuropeptide, orexin, within the medial preoptic area (mPOA) has been implicated in maternal nursing and other caregiving behaviors, we measured mPOA levels of orexin-A but it was not affected by postpartum stage or litter age (nor was there an interaction). However, high orexin-A was negatively associated with the frequency of contact with pups and the display of erect postures. These results indicate that changes in caregiving across lactation are driven by endogenous factors in the dams, age-related cues they receive from offspring, and interactions between these factors.


Sarcoidosis and adrenal angiomyolipoma - A rare tumor and a rarer coincidence.
Angiomyolipoma is a benign mesenchymal tumor occurring in about 0.3 % of the general population. Angiomyolipoma of the adrenal gland is a rare entity, and only 5 cases have been reported so far in English literature. Sarcoidosis is a systemic illness of unknown etiology characterized histologically by non-caseating epithelioid granulomas in the affected tissues. Angiomyolipoma of the adrenal occurring in sarcoidosis is an unusual association with no prior published reports. We describe a case of adrenal angiomyolipoma in a 60 year old female with sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 81-84).


Platelet responsiveness to in vitro aspirin is independent of COX-1 and COX-2 protein levels and polymorphisms.
Aspirin's inhibitory effect on platelet function has been shown to be highly heterogeneous. However, due to the considerable individual variation in pharmacokinetics after aspirin intake, it has been difficult to investigate the mechanism of aspirin resistance empirically. Our objective was to examine whether platelet responsiveness to in vitro aspirin treatment could be affected by cyclooxygenase (COX)-1/2 protein levels in platelets or single-nucleotide polymorphisms (SNPs), which could possibly change specific activity of enzymes and/or aspirin susceptibility. Collagen/epinephrine closure time (CEPI-CT) of PFA-100 in blood from 178 healthy males was assessed with/without aspirin. Platelet COX-1 protein levels and the sequences of COX-1 gene exons were examined in three groups categorized by CEPI-CT: PR (Poor responders to aspirin), 10 people showing the shortest CEPI-CT under aspirin; GR-High or GR-Low (good responders to aspirin with high or low platelet basal reactivity), 10 people showing CEPI-CT over 300 s under aspirin and having the shortest or longest basal CEPI-CT, respectively. We analyzed the three groups, representing phenotypic extremes, aiming to increase statistical power to investigate the possible relevance of COXs to platelet response to aspirin. Western blot analysis revealed that COX-1 was abundantly expressed in platelets at comparable levels among the three groups, whereas COX-2 was undetectable. The frequencies of nonsynonymous COX-1/2 SNPs were unlikely to explain the difference in aspirin responsiveness considering the observed genotype frequencies and wide individual variation in platelet response. These results suggest that heterogeneity in platelet responsiveness to in vitro aspirin is independent of COX-1/2 protein levels and SNPs.


Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells.
Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.


Effect of pesticide water pollution on some haematological, biochemical and immunological parameters in Tilapia nilotica fish.
Nine groups of Tilapia nilotica fish each consisting of 50 fish were used to assess the effect of pesticides on the haematological, biochemical and immunological parameters in fish. Four groups were injected with 0.05 ml of Staphylococcus aureus antigen plus complete Freund's adjuvant, the first group (G1) was exposed to lindane treatment, the second (G2) was exposed to dialdrin, the third (G3) was exposed to diazinon and the forth group (G4) was exposed to malathion. Four other groups were not immunized, but injected with the adjuvant and exposed to the pesticides, the fifth group (G5) was exposed to lindane, the sixth (G6) was exposed to dialdrin, the seventh (G7) was exposed to diazinon and the eighth group (G8) was exposed to malathion. The ninth group (G9) was exposed to water without any pesticide treatment and served as controls. Both vaccinated and non-vaccinated groups were exposed to 1/10 LC50 of the tested pesticides for 30 days. The results revealed that the mean total RBCs, WBCs counts, PCV, Hb, MCV, MCH, MCHC values were lower in vaccinated groups than in the groups exposed to the tested pesticides. The total protein, globulin and serum enzymes ALAT; ASAT values as well as macrophage phagocytic index and antibody titer were lower in vaccinated as compared to the non-vaccinated groups.


Effect of commercial herbal toothpastes and mouth rinses on the prevention of enamel demineralization using a microcosm biofilm model.
This work evaluated the effects of commercial toothpastes and mouth rinses containing natural/herbal agents on biofilm viability, extracellular polysaccharide (EPS) production and on enamel demineralization in vitro. Microcosm biofilm was produced on bovine enamel for 5 days and treated daily with: Orgânico natural® (toothpaste/mouth rinse), Boni Natural Menta & Malaleuca® (toothpaste/mouth rinse), Propolis & Myrrh® (toothpaste), Colgate Total 12 Clean Mint® (toothpaste, positive control), Malvatricin® Plus (mouth rinse), PerioGard® (mouth rinse, positive control) or PBS (negative control). Tom's Propolis & Myrrh® and Colgate Total 12® toothpastes and Malvatricin® Plus and PerioGard® mouth rinses significantly reduced biofilm viability (p < 0.05). Only PerioGard® had significant effects on biofilm thickness and EPS. Despite the indication that Tom's Propolis & Myrrh® significantly reduced lesion depth, only Colgate Total 12® significantly reduced mineral loss. Malvatricin® Plus significantly reduced mineral loss and lesion depth, as did PerioGard®. Some herbal products, Malvatricin® Plus and Tom's Propolis & Myrrh®, showed anticaries effects.


Association of Hospital Racial Composition and Payer Mix With Mortality in Acute Coronary Syndrome.
Background Patient characteristics insufficiently explain disparities in cardiovascular outcomes among hospitalized patients, suggesting a role for community or hospital-level factors. Here, we evaluate the association of hospital racial composition and payer mix with all-cause inpatient mortality for patients hospitalized with acute coronary syndrome (ACS). Methods and Results Using the National Inpatient Sample, we identified adult hospitalizations from 2014 with a primary diagnosis of ACS (n=550 005). We divided National Inpatient Sample hospitals into quartiles based on percent of minority (black, Hispanic, Asian or Pacific Islander, Native American race/ethnicity) and low-income payer (Medicaid or uninsured) discharges in 2014. We utilized logistic regression to determine whether hospital minority or low-income payer makeup associated with all-cause inpatient mortality among those admitted for ACS . In adjusted models, ACS patients admitted to hospitals with >12.4% to 25.4% (Quartile 2), >25.4% to 44.3% (Q3), and >44.3% (Q4) minority discharges experienced a 14% (OR 1.14, 95% CI 1.06-1.23), 13% (OR 1.13, 95% CI 1.04-1.23), and 15% (OR 1.15, 95% CI 1.04-1.26) increased odds of all-cause inpatient mortality compared with hospitals with ≤12.4% (Q1) minority discharges. ACS patients admitted to hospitals with >18.7% to 25.7% (Q2) and >34.0% (Q4) low-income payer discharges experienced a 9% (OR 1.09, 1.01-1.17) and 9% (OR 1.09, 1.00-1.19) increased odds of all-cause inpatient mortality when compared with hospitals with ≤18.7% (Q1) low-income payer discharges. Conclusions Hospital minority and low-income payer makeup positively associate with odds of all-cause inpatient mortality among patients admitted for acute coronary syndrome.


Conservative therapy as a primary treatment for spontaneous isolated dissection of the superior mesenteric artery.
Spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) is a rare and potentially fatal disease. Several therapeutic options are available, including conservative therapy, endovascular repair, and open surgery. Herein, we report our experiences in the treatment of SIDSMA. Between February 2009 and June 2013, 17 patients were diagnosed as having SIDSMA. We retrospectively reviewed and analyzed their clinical characteristics, medical history, risk factors, symptoms, diagnostic imaging modality, treatment, and outcome. The lesions were categorized according to the modified Sakamoto's classification. If no evidence of bowel necrosis or arterial rupture was present in the patients with symptomatic SIDSMA, we first performed conservative therapy, even if the patients had abdominal pain. The subjects included 15 men and 2 women, with a median age of 62.8 years. Eight patients were symptomatic and 9 were asymptomatic. Conservative therapy included the use of antithrombotic agents in 3 patients but not in 5 patients. During the follow-up period (mean, 21.1 months), all the patients were discharged without any significant complications, and none of the patients showed the progression of the dissection on follow-up computed tomography angiography examinations. Conservative therapy without antithrombotic agents should be the primary treatment for SIDSMA. Endovascular repair for SIDSMA is associated with several risks, thus the procedure might occasionally be useful and necessary.


Is remaining indoors an effective way of reducing exposure to fine particulate matter during biomass burning events?
Bushfires, prescribed burns, and residential wood burning are significant sources of fine particles (aerodynamic diameter <2.5 μm; PM2.5) affecting the health and well-being of many communities. Despite the lack of evidence, a common public health recommendation is to remain indoors, assuming that the home provides a protective barrier against ambient PM2.5. The study aimed to assess to what extent houses provide protection against peak concentrations of outdoor PM2.5 and whether remaining indoors is an effective way of reducing exposure to PM2.5. The effectiveness of this strategy was evaluated by conducting simultaneous week-long indoor and outdoor measurements of PM2.5 at 21 residences in regional areas of Victoria, Australia. During smoke plume events, remaining indoors protected residents from peak outdoor PM2.5 concentrations, but the level of protection was highly variable, ranging from 12% to 76%. Housing stock (e.g., age of the house) and ventilation (e.g., having windows/doors open or closed) played a significant role in the infiltration of outdoor PM2.5 indoors. The results also showed that leaving windows and doors closed once the smoke plume abates trapped PM2.5 indoors and increased indoor exposure to PM2.5. Furthermore, for approximately 50% of households, indoor sources such as cooking activities, smoking, and burning candles or incense contributed significantly to indoor PM2.5. Implications: Smoke from biomass burning sources can significantly impact on communities. Remaining indoors with windows and doors closed is a common recommendation by health authorities to minimize exposures to peak concentrations of fine particles during smoke plume events. Findings from this study have shown that the protection from fine particles in biomass burning smoke is highly variable among houses, with information on housing age and ventilation status providing an approximate assessment on the protection of a house. Leaving windows closed once a smoke plume abates traps particles indoors and increases exposures.


Hepatic acyl-coenzyme A:cholesterol acyltransferase activity is decreased in patients with cholesterol gallstones.
Altered hepatic cholesterol metabolism has been implicated in the etiology of cholesterol gallstones. This hypothesis has been examined by determining acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity in liver biopsies from 31 cholesterol gallstone patients and 12 control subjects. Hepatic ACAT activity in gallstone patients was decreased to one-third that in controls (P less than 0.001). No differences in hepatic homogenate or microsomal free and total cholesterol concentrations were observed between the two groups. However, marked increases in free (107%) and total (98%) cholesterol concentrations were found in the cytosolic fraction of liver biopsies from gallstone patients. The total phospholipid concentration of the liver homogenate fraction was unchanged in both groups; however, the microsomal total phospholipid concentration was reduced by 17% (P less than 0.01) in gallstone samples compared with controls. This difference did not result in a significantly increased microsomal cholesterol/phospholipid ratio for the gallstone group (0.180 +/- 0.030) compared with the control group (0.169 +/- 0.042). These results show that hepatic ACAT activity is significantly decreased in cholesterol gallstone patients. These changes in ACAT activity in livers of patients with cholesterol gallstones are consistent with the known increase in the amount of free cholesterol secreted in the bile of these patients. Thus, the changes in ACAT activity may contribute to the pathogenesis of cholesterol gallstones.


Insights into the fine architecture of the active site of chicory fructan 1-exohydrolase: 1-kestose as substrate vs sucrose as inhibitor.
* Invertases and fructan exohydrolases (FEHs) fulfil important physiological functions in plants. Sucrose is the typical substrate for invertases and bacterial levansucrases but not for plant FEHs, which are usually inhibited by sucrose. * Here we report on complexes between chicory (Cichorium intybus) 1-FEH IIa with the substrate 1-kestose and the inhibitors sucrose, fructose and 2,5 dideoxy-2,5-imino-D-mannitol. Comparisons with other family GH32 and 68 enzyme-substrate complexes revealed that sucrose can bind as a substrate (invertase/levansucrase) or as an inhibitor (1-FEH IIa). * Sucrose acts as inhibitor because the O2 of the glucose moiety forms an H-linkage with the acid-base catalyst E201, inhibiting catalysis. By contrast, the homologous O3 of the internal fructose in the substrate 1-kestose forms an intramolecular H-linkage and does not interfere with the catalytic process. Mutagenesis showed that W82 and S101 are important for binding sucrose as inhibitor. * The physiological implications of the essential differences in the active sites of FEHs and invertases/levansucrases are discussed. Sucrose-inhibited FEHs show a K(i) (inhibition constant) well below physiological sucrose concentrations and could be rapidly activated under carbon deprivation.


Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90.
Agents that inhibit Hsp90 function hold significant promise in cancer therapy. Here we present PU24FCl, a representative of the first class of designed Hsp90 inhibitors. By specifically and potently inhibiting tumor Hsp90, PU24FCl exhibits wide-ranging anti-cancer activities that occur at similar doses in all tested tumor types. Normal cells are 10- to 50-fold more resistant to these effects. Its Hsp90 inhibition results in multiple anti-tumor-specific effects, such as degradation of Hsp90-client proteins involved in cell growth, survival, and specific transformation, inhibition of cancer cell growth, delay of cell cycle progression, induction of morphological and functional changes, and apoptosis. In concordance with its higher affinity for tumor Hsp90, in vivo PU24FCl accumulates in tumors while being rapidly cleared from normal tissue. Concentrations achieved in vivo in tumors lead to single-agent anti-tumor activity at non-toxic doses.


Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies.
CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.


Biologic findings of post-traumatic stress disorder and child maltreatment.
Child maltreatment is a serious problem in US society, affecting approximately three million children. Children and adolescents exposed to child abuse and neglect experience high rates of post-traumatic stress disorder (PTSD). In addition, they are at risk for comorbid mental illness. Biologic stress systems affected in trauma and in PTSD are complex. Findings in cognitive testing, neuroimaging, and affected pathways shed light on the consequences of child maltreatment. What is known about treatment and outcomes for children with history of maltreatment and maltreatment-related PTSD indicates the need for prevention, intervention, and treatment of children exposed to abuse and neglect. The following is a brief review of the most recent neurobiologic findings in child maltreatment and related PTSD.


Quantifications and sensitivity in bone scanning in the detection of bone metastases.
In a prospective study the whole body retention (WBR) and several bone-soft-tissue ratios (BSR) were determined in 50 consecutive clinical patients. The scans were studied in the usual way. Three independent observers found an increased uptake in 5 scans. The rest activity was calculated by expressing the WBR, measured at 24 h to a percentage of the WBR measured at 5 min. It appeared that in the same 5 patients, being observed visually to show an increased uptake, the rest activity was pathologically higher than the rest activity in the 'normal' patients. The L2-flank ratio also differentiated in the five scans having the observed increased uptake. The same patients with an increased uptake were differentiated by three observers with the help of quantification. The extra use of the WBR and the BSR determinations in the detection of bone metastases appeared to be absent in this study. The sensitivity was not increased.


In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets.
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.