Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity.
The therapeutic application of siRNA shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. In this study, we have investigated whether siRNA-mediated knockdown of p38 MAP kinase mRNA in mouse lung is influenced by conjugation to the nonviral delivery vector cholesterol and the cell penetrating peptides (CPP) TAT(48-60) and penetratin. Initial studies in the mouse fibroblast L929 cell line showed that siRNA conjugated to cholesterol, TAT(48-60), and penetratin, but not siRNA alone, achieved a limited reduction of p38 MAP kinase mRNA expression. Intratracheal administration of siRNA resulted in localization within macrophages and scattered epithelial cells and produced a 30-45% knockdown of p38 MAP kinase mRNA at 6 h. As with increasing doses of siRNA, conjugation to cholesterol improved upon the duration but not the magnitude of mRNA knockdown, while penetratin and TAT(48-60) had no effect. Importantly, administration of the penetratin or TAT(48-60) peptides alone caused significant reduction in p38 MAP kinase mRNA expression, while the penetratin-siRNA conjugate activated the innate immune response. Overall, these studies suggest that conjugation to cholesterol may extend but not increase siRNA-mediated p38 MAP kinase mRNA knockdown in the lung. Furthermore, the use of CPP may be limited due to as yet uncharacterized effects upon gene expression and a potential for immune activation.


An episodic framework of outgroup interaction processing: Integration and redirection for the expatriate adjustment research.
Cross-cultural research has traditionally emphasized predicting adjustment, treating it as a level to be achieved more than a change process to be understood and controlled. The lack of focus on process integration has inhibited our understanding of precisely why and how adjustment processes unfold and ultimately cause (dys)functional change in criteria. In response, we review the motives and processes of cross-cultural adjustment and integrate these into a theoretical framework, examining the discrete episode of expatriate-host national interaction as the focal vehicle for change. First, we synthesize the general causal sequence within an interaction episode. We then summarize state inputs that condition processing. Next, we describe identity management and learning processing in depth. Then, we discuss key interactions among the motive and processing categories. Finally, we orient the cross-cultural interaction episode within the nomological network of cross-cultural adjustment predictors and criteria. This framework prescribes that an expatriate should initially reduce acculturative stress through repeated, functional identity management and learning processing of novelty encountered in cross-cultural interaction episodes. To do so, one must avoid inhibitory input states and the many potential processing failures identified here. If the expatriate experiences enough such functional interaction episodes, a "Stage 2" is reached where the motive to reduce stress has been largely overcome, and thereafter, interaction episode processing proceeds more functionally in general. (PsycINFO Database Record


Insulin-like growth factors in human breast cancer.
IGF1 and IGF2 are circulating peptide hormones and locally-acting growth factors with both paracrine and autocrine functions. IGF1 and IGF2 signal through a common tyrosine kinase receptor, the insulin-like growth factor 1 receptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and breast development. The activities of IGF1 and 2 are tightly-regulated by a network of binding proteins and targeted degradation mechanisms. This complex regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infiltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degradation; c) IGF1R is overexpressed by malignant breast epithelial cells, and in some cases IGF1R is amplified; and d) complex changes in IGF binding protein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of these findings, we propose that IGF analysis of breast cancer samples should shift from prognostic studies to an evaluation of IGF ligands, receptors, and binding proteins as resistance/sensitivity markers for radiation, chemotherapy, and endocrine therapy.


Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis.
Targeted proteomic methods can accelerate the verification of multiple tumor marker candidates in large series of patient samples. We utilized the targeted approach known as selected/multiple reaction monitoring (S/MRM) to verify potential protein markers of colorectal adenoma identified by our group in previous transcriptomic and quantitative shotgun proteomic studies of a large cohort of precancerous colorectal lesions. We developed SRM assays to reproducibly detect and quantify 25 (62.5%) of the 40 selected proteins in an independent series of precancerous and cancerous tissue samples (19 adenoma/normal mucosa pairs; 17 adenocarcinoma/normal mucosa pairs). Twenty-three proteins were significantly up-regulated (n = 17) or downregulated (n = 6) in adenomas and/or adenocarcinomas, as compared with normal mucosa (linear fold changes ≥ ±1.3, adjusted p value <0.05). Most changes were observed in both tumor types (up-regulation of ANP32A, ANXA3, SORD, LDHA, LCN2, NCL, S100A11, SERPINB5, CDV3, OLFM4, and REG4; downregulation of ARF6 and PGM5), and a five-protein biomarker signature distinguished neoplastic tissue from normal mucosa with a maximum area under the receiver operating curve greater than 0.83. Other changes were specific for adenomas (PPA1 and PPA2 up-regulation; KCTD12 downregulation) or adenocarcinoma (ANP32B, G6PD, RCN1, and SET up-regulation; downregulated AKR1B1, APEX1, and PPA1). Some changes significantly correlated with a few patient- or tumor-related phenotypes. Twenty-two (96%) of the 23 proteins have a potential to be released from the tumors into the bloodstream, and their detectability in plasma has been previously reported. The proteins identified in this study expand the pool of biomarker candidates that can be used to develop a standardized precolonoscopy blood test for the early detection of colorectal tumors.


Data-based virtual unmodeled dynamics driven multivariable nonlinear adaptive switching control.
For a complex industrial system, its multivariable and nonlinear nature generally make it very difficult, if not impossible, to obtain an accurate model, especially when the model structure is unknown. The control of this class of complex systems is difficult to handle by the traditional controller designs around their operating points. This paper, however, explores the concepts of controller-driven model and virtual unmodeled dynamics to propose a new design framework. The design consists of two controllers with distinct functions. First, using input and output data, a self-tuning controller is constructed based on a linear controller-driven model. Then the output signals of the controller-driven model are compared with the true outputs of the system to produce so-called virtual unmodeled dynamics. Based on the compensator of the virtual unmodeled dynamics, the second controller based on a nonlinear controller-driven model is proposed. Those two controllers are integrated by an adaptive switching control algorithm to take advantage of their complementary features: one offers stabilization function and another provides improved performance. The conditions on the stability and convergence of the closed-loop system are analyzed. Both simulation and experimental tests on a heavily coupled nonlinear twin-tank system are carried out to confirm the effectiveness of the proposed method.


Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury.
Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS) following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O(2)(-)), and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI. The results revealed that NADPH oxidase activity in the cerebral cortex and hippocampal CA1 region increases rapidly following controlled cortical impact in male mice, with an early peak at 1 h, followed by a secondary peak from 24-96 h after TBI. In situ localization using oxidized hydroethidine and the neuronal marker, NeuN, revealed that the O(2)(-) induction occurred in neurons at 1 h after TBI. Pre- or post-treatment with the NADPH oxidase inhibitor, apocynin markedly inhibited microglial activation and oxidative stress damage. Apocynin also attenuated TBI-induction of the Alzheimer's disease proteins β-amyloid and amyloid precursor protein. Finally, both pre- and post-treatment of apocynin was also shown to induce significant neuroprotection against TBI. In addition, a NOX2-specific inhibitor, gp91ds-tat was also shown to exert neuroprotection against TBI. As a whole, the study demonstrates that NADPH oxidase activity and superoxide production exhibit a biphasic elevation in the hippocampus and cortex following TBI, which contributes significantly to the pathology of TBI via mediation of oxidative stress damage, microglial activation, and AD protein induction in the brain following TBI.


A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion.
Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and KATP channels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca2+] in isolated β cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca2+ and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs.


Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma.
During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.


Dairy foods and dairy protein consumption is inversely related to markers of adiposity in obese men and women.
A number of intervention studies have reported that the prevalence of obesity may be in part inversely related to dairy food consumption while others report no association. We sought to examine relationships between energy, protein and calcium consumption from dairy foods (milk, yoghurt, cheese, dairy spreads, ice-cream) and adiposity including body mass index (BMI), waist (WC) and hip circumference (HC), and direct measures of body composition using dual energy X-ray absorptiometry (% body fat and abdominal fat) in an opportunistic sample of 720 overweight/obese Australian men and women. Mean (SD) age, weight and BMI of the population were 51 ± 10 year, 94 ± 18 kg and 32.4 ± 5.7 kg/m2, respectively. Reduced fat milk was the most commonly consumed dairy product (235 ± 200 g/day), followed by whole milk (63 ± 128 g/day) and yoghurt (53 ± 66 g/day). Overall dairy food consumption (g/day) was inversely associated with BMI, % body fat and WC (all p < 0.05). Dairy protein and dairy calcium (g/day) were both inversely associated with all adiposity measures (all p < 0.05). Yoghurt consumption (g/day) was inversely associated with % body fat, abdominal fat, WC and HC (all p < 0.05), while reduced fat milk consumption was inversely associated with BMI, WC, HC and % body fat (all p < 0.05). Within a sample of obese adults, consumption of dairy products, dairy protein, and calcium was associated with more favourable body composition.


Patients with severe asymptomatic carotid artery stenosis do not have a higher risk of stroke and mortality after coronary artery bypass surgery.
Stroke development is a major concern in patients undergoing coronary artery bypass grafting (CABG). Whether asymptomatic severe carotid artery stenosis (CAS) contributes to the development of stroke and mortality in such patients remains uncertain. A retrospective analysis of 878 consecutive patients with documented carotid duplex ultrasound who underwent isolated CABG in our institution from January 2003 to December 2009 was performed. Patients with severe CAS (n=117) were compared with those without severe CAS (n=761) to assess the rates of stroke and mortality during hospitalization for CABG. The 30-day mortality rate was also assessed. Patients with severe CAS were older and had a higher prevalence of peripheral arterial disease and heart failure. Patients with severe CAS had similar rates of in-hospital stroke (3.4% versus 3.6%; P=1.0) and mortality (3.4% versus 4.2%; P=1.0) compared with patients without severe CAS. The 30-day rate of mortality was also similar between the 2 cohorts (3.4% versus 2.9%; P=0.51). Severe CAS alone is not a risk factor for stroke or mortality in patients undergoing CABG. The decision to perform carotid imaging and subsequent revascularization in association with CABG must be individualized and based on clinical judgment.


Current and future trends in demographics of veterinary medicine in California.
To evaluate the present and future supply of veterinarians in California, in light of changing trends in animal ownership. Database analysis. Human and animal populations, including populations of veterinarians, throughout the United States. Data on animal and human populations were compiled from a number of sources, including the US Census Bureau, American Veterinary Medical Association, State of California Department of Finance, and State of California Veterinary Medical Board. The distribution of veterinarians in California was contrasted with other health professionals in California and with that of veterinarians in other states. Recent changes in veterinary medical demographics in California were quantified and used to develop in-state projections about the supply of veterinarians for the next 20 years. Although California is the most populous of the 50 states, only 7 states had fewer veterinarians per capita. Furthermore, California ranked next to last among states in increase of number of veterinarians between 1990 and 1995. Los Angeles County had the smallest per-capita number of veterinarians among 9 populous California counties. During that period, California had a net gain of only 6 veterinarians who were exclusively or predominantly large-animal or mixed-animal practitioners. If current trends continue, the per-capita number of veterinarians will continue to decrease in California. To maintain the current ratio of 17.8 veterinarians/100,000 people in California in the future, we estimate that an additional 50 veterinarians above the currently predicted increase will be required annually.


Non-uniform central airways ventilation model based on vascular segmentation.
Improvements in the understanding of the physiology of the central airways require an appropriate representation of the non-uniform ventilation at its terminal branches. This paper proposes a new technique for estimating the non-uniform ventilation at the terminal branches by modelling the volume change of their distal peripheral airways, based on vascular segmentation. The vascular tree is used for sectioning the dynamic CT-based 3D volume of the lung at 11 time points over the breathing cycle of a research animal. Based on the mechanical coupling between the vascular tree and the remaining lung tissues, the volume change of each individual lung segment over the breathing cycle was used to estimate the non-uniform ventilation of its associated terminal branch. The 3D lung sectioning technique was validated on an airway cast model of the same animal pruned to represent the truncated dynamic CT based airway geometry. The results showed that the 3D lung sectioning technique was able to estimate the volume of the missing peripheral airways within a tolerance of 2%. In addition, the time-varying non-uniform ventilation distribution predicted by the proposed sectioning technique was validated against CT measurements of lobar ventilation and showed good agreement. This significant modelling advance can be used to estimate subject-specific non-uniform boundary conditions to obtain subject-specific numerical models of the central airway flow.


Cesarean sections in a birth center.
To estimate the prevalence of cesarean sections in a birth center of a hospital and identify factors associated. Cross-sectional study including medical records of 2,441 births assisted in a birth center in the city of São Paulo, southeastern Brazil, between March and April 2005. The dependent variable (type of delivery) included vaginal delivery and cesarean section. The independent variables were grouped into four categories: demographic characteristics; current and past obstetric history; intrapartum care; and perinatal outcomes. Prevalence ratios and 95% confidence intervals (95% CI) were estimated to assess the association between type of delivery and maternal and newborn variables. Of all deliveries, 14.9% were cesarean sections. Cesarean section in the current pregnancy was associated with past cesarean sections (PR = 3.19, 95%CI: 2.64,3.84); gestational age > 40 weeks (PR = 1.32, 95%CI: 1.09;1.61); cervical dilation of up to 4 cm on admission (PR = 3.22, 95%CI: 2.31;4.50); and meconium-stained amniotic fluid (PR = 2.5, 95%CI: 2.05;3.06). Regarding newborn characteristics cesarean section was associated with birth weight >4 kg (PR = 1.86, 95%CI: 1.29;2.66). Among women with history of past cesarean sections, having had also a prior vaginal delivery was a protective factor for cesarean section in the current pregnancy (PR = 0.46, 95%CI: 0.30;0.71). Factors related to fetal conditions including fetal stress, meconium-stained amniotic fluid, breech presentation and macrosomia accounted for 47.8% (175) while those related to the mechanism of birth including arrest disorders, functional dystocia and malposition accounted for 31,3% (115) of all indications for a cesarian section [corrected]. Prevalence of c-section was consistent with World Health Organization recommendations. Increased risk of c-section was associated with prior history of c-sections, cervical dilation of at least 4 cm upon admission, gestational age > 40 weeks, meconium-stained amniotic fluid, and birthweight > 4 kg.


Dynamics on the laminar-turbulent boundary and the origin of the maximum drag reduction asymptote.
Dynamical trajectories on the boundary in state space between laminar and turbulent plane channel flow-edge states-are computed for Newtonian and viscoelastic fluids. Viscoelasticity has a negligible effect on the properties of these solutions, and, at least at a low Reynolds number, their mean velocity profiles correspond closely to experimental observations for polymer solutions in the maximum drag reduction regime. These results confirm the existence of weak turbulence states that cannot be suppressed by polymer additives, explaining the fact that there is an upper limit for polymer-induced drag reduction.


Validity of the Stages of Change in Steps instrument (SoC-Step) for achieving the physical activity goal of 10,000 steps per day.
Physical activity (PA) offers numerous benefits to health and well-being, but most adults are not sufficiently physically active to afford such benefits. The 10,000 steps campaign has been a popular and effective approach to promote PA. The Transtheoretical Model posits that individuals have varying levels of readiness for health behavior change, known as Stages of Change (Precontemplation, Contemplation, Preparation, Action, and Maintenance). Few validated assessment instruments are available for determining Stages of Change in relation to the PA goal of 10,000 steps per day. The purpose of this study was to assess the criterion-related validity of the SoC-Step, a brief 10,000 steps per day Stages of Change instrument. Participants were 504 Australian adults (176 males, 328 females, mean age = 50.8 ± 13.0 years) from the baseline sample of the Walk 2.0 randomized controlled trial. Measures included 7-day accelerometry (Actigraph GT3X), height, weight, and self-reported intention, self-efficacy, and SoC-Step: Stages of Change relative to achieving 10,000 steps per day. Kruskal-Wallis H tests with pairwise comparisons were used to determine whether participants differed by stage, according to steps per day, general health, body mass index, intention, and self-efficacy to achieve 10,000 steps per day. Binary logistic regression was used to test the hypothesis that participants in Maintenance or Action stages would have greater likelihood of meeting the 10,000 steps goal, in comparison to participants in the other three stages. Consistent with study hypotheses, participants in Precontemplation had significantly lower intention scores than those in Contemplation (p = 0.003) or Preparation (p < 0.001). Participants in Action or Maintenance stages were more likely to achieve ≥10,000 steps per day (OR = 3.11; 95 % CI = 1.66,5.83) compared to those in Precontemplation, Contemplation, or Preparation. Intention (p < 0.001) and self-efficacy (p < 0.001) to achieve 10,000 steps daily differed by stage, and participants in the Maintenance stage had higher general health status and lower body mass index than those in Precontemplation, Contemplation and Preparation stages (p < 0.05). This brief SoC-Step instrument appears to have good criterion-related validity for determining Stages of Change related to the public health goal of 10,000 steps per day. Australian New Zealand Clinical Trials Registry reference: ACTRN12611000157976 World Health Organization Universal Trial Number: U111-1119-1755.


Diffraction phase and fluorescence microscopy.
We have developed diffraction phase and fluorescence (DPF) microscopy as a new technique for simultaneous quantitative phase imaging and epi-fluorescence investigation of live cells. The DPF instrument consists of an interference microscope, which is incorporated into a conventional inverted fluorescence microscope. The quantitative phase images are characterized by sub-nanometer optical path-length stability over periods from milliseconds to a cell lifetime. The potential of the technique for quantifying rapid nanoscale motions in live cells is demonstrated by experiments on red blood cells, while the composite phase-fluorescence imaging mode is exemplified with mitotic kidney cells.


Dual effect of a polymorphism in the macrophage migration inhibitory factor gene is associated with new-onset Graves disease in a Taiwanese Chinese population.
Graves disease (GD) is an autoimmune disease. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Two polymorphisms in the promoter region of MIF, rs5844572 and rs755622, are known to affect MIF expression. The purpose of this study was to investigate the relationship between polymorphisms in the MIF gene promoter and the severity of GD. A total of 677 individuals, including 481 GD patients and 196 ethnically matched healthy controls, were genotyped to identify differences in the distribution of the MIF polymorphisms rs5844572 and rs755622. Although there were no significant differences in the allele or genotype distributions among patients with different grades of goiter in GD and healthy controls, the distribution of the C allele, especially C/C genotype, of the rs755622 single nucleotide polymorphism (SNP) in MIF, may be as a risk factor for goiter initiation whereas a protector against development of severe goiter in patients with untreated GD (p<0.05). A goiter-developmental model incorporating genetic (MIF SNP rs755622) and environmental risk factors (gender, radioiodine treatment, thyroid gland surgery and vitiligo) significantly increased the prediction accuracy. Further studies are required to address the role of MIF polymorphisms, as well as their association with other candidate genes, in GD.


Feasibility and Acceptability of the 'HABIT' Group Programme for Comorbid Bipolar and Alcohol and Substance use Disorders.
We investigated the feasibility and acceptability of an integrated group therapy (called HABIT) for comorbid bipolar disorder (BD) and alcohol and substance use disorders (ASUD) (BD-ASUD), a disabling clinical presentation for which no specific treatment has been validated. The 14-session HABIT programme employs psychoeducation-oriented cognitive-behaviour therapy (CBT) followed by mindfulness-based relapse prevention (MBRP) therapy. Potential group participants were recruited from adult clients with a DSM-IV diagnosis of BD and an ASUD who were referred by their treating clinician. Observer-rated changes in mood symptoms and ASUD, attendance rates and subjective feedback are reported. Eight of 12 clients referred to the programme initially agreed to join the group, six attended the first group session and five clients completed the programme. Group mean scores for mood symptoms improved over time, with slightly greater reductions in depression during the first module. About 50% of individuals showed clinically significant improvement (≥30% reduction) in alcohol and substance use. Attendance rates showed some variability between individuals and across sessions, but the average attendance rate of the group was marginally higher for the first module (86%) as compared with the second module (77%). Most clients reported high levels of general satisfaction with a group specifically targeted at individuals with BD-ASUD. This small pilot study suggests our intensive group therapy is acceptable and feasible. If findings are replicated, we may have identified a therapy that, for the first time, leads to improvement in both mood and substance use outcomes in clients with difficult-to-treat comorbid BD-ASUD. Copyright © 2016 John Wiley & Sons, Ltd. Key Practitioner Message Comorbidity between bipolar and alcohol and substance use disorders (BD-ASUD) is frequent and highly disabling; Therapeutic research on approaches that can simultaneously help BD and ASUD is lacking; Previous research highlights the need for integrated treatment of both conditions but showed improvements limited to either element of the comorbid disorder; This pilot study supports the feasibility and acceptability of an intensive, 14-session group therapy programme that integrates CBT and mindfulness approaches.


Cylindrical cloaking at oblique incidence with optimized finite multilayer parameters.
We propose multilayer cylindrical invisibility cloaks that are optimized for oblique incidences through a combination of analytic formalism of scattering and genetic optimization. We show that by using only four layers of homogeneous and anisotropic metamaterials without large values of constitutive parameters, the scattering for oblique incidences can be reduced by 2 orders. Although the optimization is done at a single incident angle, the cloak provides reduced scattering over a large range of incident angles.


Sequence of three bronze alleles of maize and correlation with the genetic fine structure.
The genomic sequences of three bronze alleles from Zea mays, Bz-McC, Bz-W22 and bz-R, are presented together with their flanking sequences. The bronze locus encodes UDPglucose flavonoid glucosyl-transferase (UFGT), an anthocyanin biosynthetic enzyme. The wild-type alleles Bz-McC and Bz-W22 condition purple phenotypes in the seed and plant, while bz-R conditions a bronze color. A full length cDNA corresponding to the Bz-McC allele was cloned and sequenced. Primer extension and RNase protection experiments were used to verify the 5' end of the bronze transcript. The Bz-McC allele has a 1416-bp coding region, a 100-bp intron and an approximately 83-bp 5' leader. Upstream of the message initiation site the sequences CTAACT and AATAAA occupy the positions where the eukaryotic consensus CCAAT and TATA boxes are normally found. The alleles Bz-McC and bz-R each have different large insertions with characteristics of transposable elements in their 5' flanking regions. The bz-R allele is distinguished by a 340-bp deletion starting within the intron and including 285 bp of the second exon. The Bz-McC and Bz-W22 isoalleles are known to differ in two genetically defined locations. The uts and uqv sites from the Bz-McC allele condition, respectively, lowered thermostability for the UFGT enzyme and increased amount of UFGT activity when compared with the corresponding sites in the Bz-W22 allele. The uts site maps to a region of the gene encoding two adjacent amino acid differences, either or both of which might alter the thermostability of the UFGT enzyme. The difference in UFGT levels conditioned by the uqv site is shown here to be correlated with variation in the bronze mRNA level. A likely cause of this decreased bronze mRNA level in Bz-W22 is a 6-bp duplication near the sequence CTAACT located 74 bp upstream of the bronze message initiation site. This region is therefore tentatively identified as the uqv site.


Top-down and bottom-up approaches to transparent, flexible and luminescent nitrogen-doped carbon nanodot-clay hybrid films.
Two easy approaches are successfully employed for the preparation of nitrogen-doped carbon nanodot (NCND)-clay hybrids (bulk solids and thin films). Fluorescent and small NCNDs are intercalated within the interlayer space of LAPONITE® clay with a simple ion exchange reaction in bulk or embedded between functionalized LAPONITE® sheets by combining a layer-by-layer approach with a self-assembly process. In both cases, homogeneous hybrids with 2D-ordered NCNDs (accounting for >20 wt%) are produced, with the NCND optoelectronic properties preserved. Drop casting of suspensions or self-assembly on flexible substrates allows the fabrication of luminescent flexible films. The transparency of the films is found to be adjustable either by controlling the concentration of the drop-cast suspensions or by the number of layers in the self-assembly procedure. The prepared films are stable over time: the inert LAPONITE® platelets not only guide the highly ordered 2D assemblies of NCNDs in the interlayer space but also protect them from external agents, which could affect their surfaces and thus alter their optoelectronic properties.


Glycosylation of PrPC determines timing of neuroinvasion and targeting in the brain following transmissible spongiform encephalopathy infection by a peripheral route.
Transmissible spongiform encephalopathy (TSE) infectivity naturally spreads from site of entry in the periphery to the central nervous system where pathological lesions are formed. Several routes and cells within the host have been identified as important for facilitating the infectious process. Expression of the glycoprotein cellular PrP (PrP(C)) is considered a key factor for replication of infectivity in the central nervous system (CNS) and its transport to the brain, and it has been suggested that the infectious agent propagates from cell to cell via a domino-like effect. However, precisely how this is achieved and what involvement the different glycoforms of PrP have in these processes remain to be determined. To address this issue, we have used our unique models of gene-targeted transgenic mice expressing different glycosylated forms of PrP. Two TSE strains were inoculated intraperitoneally into these mice to assess the contribution of diglycosylated, monoglycosylated, and unglycosylated PrP in spreading of infectivity to the brain. This study demonstrates that glycosylation of host PrP has a profound effect in determining the outcome of disease. Lack of diglycosylated PrP slowed or prevented disease onset after peripheral challenge, suggesting an important role for fully glycosylated PrP in either the replication of the infectious agent in the periphery or its transport to the CNS. Moreover, mice expressing unglycosylated PrP did not develop clinical disease, and mice expressing monoglycosylated PrP showed strikingly different neuropathologic features compared to those expressing diglycosylated PrP. This demonstrates that targeting in the brain following peripheral inoculation is profoundly influenced by the glycosylation status of host PrP.


Quality of life assessment in advanced non-small-cell lung cancer patients undergoing an accelerated radiotherapy regimen: report of ECOG study 4593. Eastern Cooperative Oncology Group.
To prospectively evaluate the quality of life (QOL) before, at completion, and after therapy for patients receiving an accelerated fractionation schedule of radiotherapy for advanced, unresectable non-small-cell lung cancer in a Phase II multi-institutional trial. The Functional Assessment of Cancer Therapy-Lung (FACT-L) patient questionnaire was used to score the QOL in patients enrolled in the Eastern Cooperative Oncology Group Phase II trial (ECOG 4593) of hyperfractionated accelerated radiotherapy in non-small-cell lung cancer. Radiotherapy (total dose 57.6 Gy in 36 fractions) was delivered during 15 days, with three radiation fractions given each treatment day. The protocol was activated in 1993, and 30 patients had accrued by November 1995. The FACT-L questionnaire was administered at study entry (baseline), on the last day of radiotherapy (assessment 2), and 4 weeks after therapy (assessment 3). The FACT-L includes scores for physical, functional, emotional, and social well-being (33 items), and a subscale of lung cancer symptoms (10 additional items). The summation of the physical, functional, and lung cancer symptom subscales (21 items) constitutes the Trial Outcome Index (TOI), considered the most clinically relevant outcome measure in lung cancer treatment trials. The FACT-L completion rates at the designated study time points were as follows: baseline, 30 of 30 (100%); assessment 2, 29 (97%) of 30; and assessment 3, 24 (80%) of 30. At treatment completion, statistically significant declines in QOL scores were noted, compared with baseline for physical and functional well-being. Emotional well-being scores improved at both assessment 2 and assessment 3. The physical and functional scores returned approximately to baseline values at assessment 3. The change in TOI score was evaluated as a function of the clinical response to treatment, toxicity grade, and survival; no clear association was noted. A trend for the largest decrease in QOL was noted for patient groups with shorter survival times. The mean change in the TOI score from baseline to assessment 3 was -8.96 for patients surviving < 52 weeks vs. -0.95 for those surviving > 52 weeks. The FACT-L questionnaire can be successfully administered to non-small-cell lung cancer patients enrolled in a prospective Phase II trial of accelerated radiation fractionation. The decrement in physical and functional QOL during treatment returned to baseline level at 4 weeks after treatment. Emotional well-being improved at all time points. A trend was noted for shorter survival times in patients with the largest negative change in TOI score. These data suggest that the clinical use of hyperfractionated accelerated radiotherapy did not cause a significant, long-term decrease in the QOL of the treated patients, and that it is feasible to perform a QOL study of patients enrolled in such a trial.


Comparison the efficacy of ablative CO2 laser and fractional CO2 laser on the healing of cutaneous leishmaniasis scars.
The aim of this study is to compare ablative CO2 laser with fractional CO2 laser on healing of the wound and the size of cutaneous leishmaniasis scars. This prospective randomized clinical trial study was done on 120 patients in two groups evaluated in Sedigheh Tahereh Hospital in Isfahan. The patients in case group underwent one session ablative CO2 laser for treatment of leishmaniasis scars and the patients in control group underwent six 3-weeks interval sessions fractional CO2 laser for treatment of leishmaniasis scars. All cases were evaluated from size and other aspects of scar by a questionnaire, and before and 6 months after photos were evaluated by blinded dermatologist. The data collected in the check list was then analyzed by t-test and Chi-square with SPSS 20. There were 60 people in case group and 60 in control group. The mean age was 27.21 ± 11.2. Our results show that fractional CO2 laser is better than ablative CO2 laser in various aspect of treatment of leishmaniasis scars (P < 0.05). Fractional CO2 laser is better than ablative CO2 laser in variants aspect of treatment of leishmaniasis scars.


Self-Management and Self-Management Support Outcomes: A Systematic Review and Mixed Research Synthesis of Stakeholder Views.
Self-management has received growing attention as an effective approach for long-term condition management. Little is known about which outcomes of supported self-management are valued by patients, their families, health professionals and those who commission self-management services. This study systematically reviewed published empirical evidence in accordance with PRISMA guidelines to determine the outcomes of self-management valued by these key stakeholder groups, using three prominent exemplar conditions: colorectal cancer, diabetes and stroke. To systematically review the literature to identify which generic outcomes of self-management have been targeted and are considered important using three exemplar conditions (colorectal cancer, diabetes and stroke), which collectively have a range of features that are likely to be representative of generic self-management issues. Systematic searching of nine electronic databases was conducted in addition to hand searches of review articles. Abstracts were identified against inclusion criteria and appraised independently by two reviewers, using a critical appraisal tool. Synthesis of findings was conducted using mixed research synthesis. Over 20,536 abstracts were screened. 41 studies which met the review criteria were fully retrieved and appraised. The majority of evidence related to diabetes. Few studies directly focussed on stakeholders' views concerning desired self-management outcomes; the majority of evidence was derived from studies focusing upon the experience of self-management. The views of health care commissioners were absent from the literature. We identified that self-management outcomes embrace a range of indicators, from knowledge, skills, and bio-psychosocial markers of health through to positive social networks. Patients', families', health professionals' and commissioners' views regarding which outcomes of self-management are important have not been clearly elicited. The extent to which bio-psychosocial indicators relate to successful self-management from the perspectives of all groups of stakeholders is unknown. Further investigation regarding which self-management outcomes are considered important by all stakeholders is necessary to guide the commissioning and design of future self-management services.


Multicenter survey with a systematic overview of acute-onset endophthalmitis after transconjunctival microincision vitrectomy surgery.
To explore the incidence and visual outcomes of acute-onset endophthalmitis after transconjunctival microincision vitrectomy surgery (MIVS). Retrospective, interventional, multicenter survey with a systematic review. A clinical database search was performed at 27 institutions involving 43 868 consecutive patients who underwent vitrectomy between November 2003 and October 2008 to identify all patients with endophthalmitis after vitrectomy. A systematic review of studies reporting the endophthalmitis rates after MIVS versus 20-gauge vitrectomy was conducted to assess the pooled incidence rates of postvitrectomy endophthalmitis. The endophthalmitis rates from the multicenter survey were 0.034% (10 cases per 29 030 eyes) after 20-gauge vitrectomy and 0.054% (8 cases per 14 838 eyes) after MIVS, with no significant (P = .603) differences between groups. Although the incidence in 25-gauge cases (6 per 8238 eyes; 0.073%) was greater than in 23-gauge cases (2 per 6600 eyes; 0.030%), the difference was not significant (P = 0.451). Of 8 eyes in which endophthalmitis developed after MIVS, 6 eyes (75%) had a final visual acuity of 0.5 or better, and none lost light perception. By combining the results of 7 studies, including the current multicenter survey, meta-analyses from a total of 77 956 cases at the baseline showed that the pooled endophthalmitis rates after MIVS (0.08%; 95% confidence interval, 0.030% to 0.164%) and after 20-gauge vitrectomy (0.030%; 95% confidence interval, 0.012% to 0.048%) did not differ significantly (P = .207, pooled risk difference; 0.0005 [95% confidence interval, -0.0002 to 0.0012]). The incidence of postvitrectomy endophthalmitis was low with no significant differences between MIVS and 20-gauge vitrectomy.


Diverse mechanisms of IRF5 action in inflammatory responses.
Interferon regulatory factor 5 (IRF5) is a key signal-dependent transcription factor in myeloid cells. Its expression is induced by granulocyte-macrophage colony stimulating factor and interferon-gamma. IRF5 protein is further activated in response to stimulation, translocating to the nucleus where it mediates inflammatory responses. IRF5 is capable of both the up-regulation of pro-inflammatory genes and repressing anti-inflammatory mediators, thus polarising macrophages to a pro-inflammatory phenotype. We discuss IRF5 interactions with a wide range of transcriptional regulators that give rise to its diverse effects at the level of chromatin.


High Precision Location Estimation in Mountainous Areas Using GPS.
Outdoor recreation has become popular in recent years, against the backdrop of the new coronavirus epidemic that started in 2020. Mountaineering, in particular, has become a popular pastime for many people as an easy way to experience nature. However, the number of mountaineering accidents is increasing, owing to the inadequate knowledge and equipment for beginners. In particular, the lack of map-reading skills and experience often leads to the selection of wrong trails. The smartphones used for precise location information obtain correction information from radio waves from a base station, and the accuracy of using only the GPS in mountainous areas without radio waves is questionable. In general, the GPS position correction methods in the literature for such situations include complex processing of the GPS radio waves. Some of these methods have been proposed with complex hardware and are difficult to implement with portable hardware. In this study, we develop and demonstrate a method for obtaining accurate location information using GPS without the error correction of radio waves, even in mountainous areas. The multipath is the reason for most of the GPS errors in the mountains. In the mountains, depending on the locations, the correct GPS location can also be received. In the proposed method, the correct GPS data are used to detect the incorrect GPS locations. We present an experimental method for estimating the interrelationship between the GPS longitude and latitude data. Additionally, we demonstrate the effectiveness of our method by showing that the experimental mountain location data presented in this paper are more accurate than the GPS data alone.


Time Spent by Intensive Care Unit Nurses on the Electronic Health Record.
The amount of time spent on the electronic health record is often cited as a contributing factor to burnout and work-related stress in nurses. Increased electronic health record use also reduces the time nurses have for direct contact with patients and families. There has been minimal investigation into the amount of time intensive care unit nurses spend on the electronic health record. To quantify the amount of time spent by intensive care unit nurses on the electronic health record. In this observational study, active electronic health record use time was analyzed for 317 intensive care unit nurses in a single institution from January 2019 through July 2020. Monthly data on electronic health record use by nurses in the medical, neurosurgical, and surgical-trauma intensive care units were evaluated. Full-time intensive care unit nurses spent 28.9 hours per month on the electronic health record, about 17.5% of their clinical shift, for a total of 346.3 hours per year. Part-time nurses and those working as needed spent 20.5 hours per month (17.6%) and 7.4 hours per month (14.2%) on the electronic health record, respectively. Neurosurgical and medical intensive care unit nurses spent 25.0 hours and 19.9 hours per month, respectively. Nurses averaged 23 clicks per minute during use. Most time was spent on the task of documentation at 12.3 hours per month, which was followed by medical record review at 2.6 hours per month. Intensive care unit nurses spend at least 17% of their shift on the electronic health record, primarily on documentation. Future interventions are necessary to reduce time spent on the electronic health record and to improve nurse and patient satisfaction.


The impact of filtered water-pipe smoke on healthy versus cancer cells and their neurodegenerative role on AMPA receptor.
Water pipe smoking is highly prevalent in developing countries, especially in Eastern Mediterranean regions. Research finds that more than 100 million people smoke a water pipe. Furthermore, tobacco smoking is one of the leading behavioral factors related to an increased risk of cancer, a leading cause of death globally. We aim to introduce a novel filtration system for water-pipe smoking and evaluate cytotoxic effects of common water pipe condensed smoke in comparison with our novel filtration system on normal (HEK293t) and cancer cell lines (Hep3B and MCF7) by MTS assay, alpha-fetoprotein (aFP), and apoptosis/necrosis effects. More so, the smoke substituents' neurotoxicity effect was evaluated by analyzing the depressive property on AMPA receptors (AMPARs). Our results showed that the silica filtration system was more effective than the water filtration system. The number of toxic compounds was reduced from 145 mg in distilled water extract (DWE) to 57.5 mg in silica solution extract (SSE). The SSE method also showed lower toxicity impacts on normal and cancerous cell lines (HEK293t, Hep3B, and MCF7) with CC50 values 149.9, 10.14, and 8.9 µg/ml, relative to the DWE method (CC50 values 77.1, 3.1, and 5.24 µg/ml, respectively). SSE extraction also reduced the α-FP (tumor marker test) to 2273.3 ng/ml which was closer in value to untreated cells (4066.7 ng/ml) in comparison with DWE which reduced it greatly to 1658.7 ng/ml, and the biophysical properties of AMPAR subunits demonstrate a reduced effect on desensitization rates of GluA2 homomer and GluA1/2 heteromer, using SSE relative to DWE. In conclusion, the condensed smoke of ordinary water pipe (DWE) has cytotoxic and neurotoxic impacts on various cell lines, while our newly developed system (SSE) was less toxic.


miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression.
Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes. We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts. Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases in lipogenesis and lipid accumulation-related transcripts. Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype. Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.


Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL.
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability. HIF-1 alpha is the oxygen-regulated subunit of HIF-1, an alpha beta heterodimeric complex. HIF-1 alpha is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex. Capture of HIF-1 alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1 alpha. The crystal structure of a hydroxylated HIF-1 alpha peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.


The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes.
The branched-chain amino acid (BCAA) leucine has been identified to be a key regulator of skeletal muscle anabolism. Activation of anabolic signalling occurs via the mammalian target of rapamycin (mTOR) through an undefined mechanism. System A and L solute carriers transport essential amino acids across plasma membranes; however it remains unknown whether an exogenous supply of leucine regulates their gene expression. The aim of the present study was to investigate the effects of acute and chronic leucine stimulation of anabolic signalling and specific amino acid transporters, using cultured primary human skeletal muscle cells. Human myotubes were treated with leucine, insulin or co-treated with leucine and insulin for 30 min, 3 h or 24 h. Activation of mTOR signalling kinases were examined, together with putative nutrient sensor human vacuolar protein sorting 34 (hVps34) and gene expression of selected amino acid transporters. Phosphorylation of mTOR and p70S6K was transiently increased following leucine exposure, independently to insulin. hVps34 protein expression was also significantly increased. However, genes encoding amino acid transporters were differentially regulated by insulin and not leucine. mTOR signalling is transiently activated by leucine within human myotubes independently of insulin stimulation. While this occurred in the absence of changes in gene expression of amino acid transporters, protein expression of hVps34 increased.


The impact of sex offender residence restrictions: 1,000 feet from danger or one step from absurd?
Several states have enacted public policies that prohibit sex offenders who have abused children from living within close proximity to a school, park, day care center, or school bus stop. The purpose of this exploratory study was to describe the impact of residence restrictions on sex offender reintegration and to better understand sex offenders' perceptions of these laws. A survey of 135 sex offenders in Florida was conducted. Most of the molesters who responded to the survey indicated that housing restrictions increased isolation, created financial and emotional stress, and led to decreased stability. Respondents also indicated that they did not perceive residence restrictions as helpful in risk management and, in fact, reported that such restrictions may inadvertently increase triggers for reoffense. Implications for policy and practice are discussed.


ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis.
Because Bcl-2 family members inhibit the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis, we investigated whether ABT-737, a small molecule Bcl-2 inhibitor, enhances TRAIL killing. We demonstrate that a combination of ABT-737 and TRAIL induced significant cell death in multiple cancer types, including renal, prostate, and lung cancers, although each agent individually had little activity in these tumor cells. All of these cell lines expressed the Mcl-1 protein that is known to block the activity of ABT-737 and TRAIL but did not block the synergy between these agents. However, Bax-deficient cell lines, including DU145 and HCT116 cells and those cell lines expressing low levels of TRAIL receptor, were resistant to apoptosis induced by these agents. To understand how ABT-737 functions to markedly increase TRAIL sensitivity, the levels of specific death-inducing signaling complex components were evaluated. Treatment with ABT-737 did not change the levels of c-FLIP, FADD, and caspase-8 but up-regulated the levels of the TRAIL receptor DR5. DR5 up-regulation induced by ABT-737 treatment occurred through a transcriptional mechanism, and mutagenesis studies demonstrated that the NF-kappaB site found in the DR5 promoter was essential for the ability of ABT-737 to increase the levels of this mRNA. Using luciferase reporter plasmids, ABT-737 was shown to stimulate NF-kappaB activity. Together, these results demonstrate that the ability of ABT-737 and TRAIL to induce apoptosis is mediated through activation of both the extrinsic and intrinsic pathways. Combinations of ABT-737 and TRAIL can be exploited therapeutically where antiapoptotic Bcl-2 family members drive tumor cell resistance to current anticancer therapies.


Three-Dimensional Echocardiography for Transcatheter Aortic Valve Replacement Sizing: A Systematic Review and Meta-Analysis.
Background Transcatheter aortic valve replacement (TAVR) is the standard of care for many patients with severe symptomatic aortic stenosis and relies on accurate sizing of the aortic annulus. It has been suggested that 3-dimensional transesophageal echocardiography (3D TEE) may be used instead of multidetector computed tomography (MDCT) for TAVR planning. This systematic review and meta-analysis compared 3D TEE and MDCT for pre-TAVR measurements. Methods and Results A systematic literature search was performed. The primary outcome was the correlation coefficient between 3D TEE- and MDCT-measured annular area. Secondary outcomes were correlation coefficients for mean annular diameter, annular perimeter, and left ventricular outflow tract area; interobserver and intraobserver agreements; mean differences between 3D TEE and MDCT measurements; and pooled sensitivities, specificities, and receiver operating characteristic area under curve values of 3D TEE and MDCT for discriminating post-TAVR paravalvular aortic regurgitation. A random effects model was used. Meta-regression and leave-one-out analysis for the primary outcome were performed. Nineteen studies with a total of 1599 patients were included. Correlations between 3D TEE and MDCT annular area, annular perimeter, annular diameter, and left ventricular outflow tract area measurements were strong (0.86 [95% CI, 0.80-0.90]; 0.89 [CI, 0.82-0.93]; 0.80 [CI, 0.70-0.87]; and 0.78 [CI, 0.61-0.88], respectively). Mean differences between 3D TEE and MDCT between measurements were small and nonsignificant. Interobserver and intraobserver agreement and discriminatory abilities for paravalvular aortic regurgitation were good for both 3D TEE and MDCT. Conclusions For pre-TAVR planning, 3D TEE is comparable to MDCT. In patients with renal dysfunction, 3D TEE may be potentially advantageous for TAVR measurements because of the lack of contrast exposure.


The Missing Link between Juvenile Delinquency and Pediatric Posttraumatic Stress Disorder: An Attachment Theory Lens.
The present paper reviews pediatric posttraumatic stress disorder, emphasizing the relational basis of the disorder and highlighting the missing link between juvenile delinquency and trauma. The first part of the paper defines trauma and the diagnostic criteria for PTSD, noting child-specific features. The second part reviews the literature emphasizing the relational and attachment relevant nature of trauma. The third part explores psychological mechanisms for how attachment relations could affect trauma responses. Attachment relations (1) shape core schemas of the world, others, and the self and (2) foster emotional engagement or disengagement, both of which have been associated with traumatic responses. The most empirically supported pediatric trauma treatment, trauma-focused cognitive behavioral therapy (TF-CBT), acknowledges the attachment figure's influence and includes treating and training the parent and conjoint child-parent discussion. The next section reviews the noteworthy link between juvenile delinquency and trauma history. More awareness of trauma and PTSD in children and adolescents is recommended to effectively address juvenile delinquency. The review ends with a few helpful points for practicing pediatricians regarding childhood trauma.


Highly efficient deep UV generation by four-wave mixing in gas-filled hollow-core photonic crystal fiber.
We report on a highly efficient experimental scheme for the generation of deep-ultraviolet (UV) ultrashort light pulses using four-wave mixing in gas-filled kagomé-style photonic crystal fiber. By pumping with ultrashort, few microjoule pulses centered at 400 nm, we generate an idler pulse at 266 nm and amplify a seeded signal at 800 nm. We achieve remarkably high pump-to-idler energy conversion efficiencies of up to 38%. Although the pump and seed pulse durations are ∼100 fs, the generated UV spectral bandwidths support sub-15 fs pulses. These can be further extended to support few-cycle pulses. Four-wave mixing in gas-filled hollow-core fibers can be scaled to high average powers and different spectral regions such as the vacuum UV (100-200 nm).


Design and simulation of an automatic room heater control system.
This paper presents the design and simulation of an Automatic Room Heater Control system. This system allows the user to set a desired temperature which is then compared to the room temperature measured by a temperature sensor. With the help of a microcontroller, the system responds by turning ON any of the two (2) loads (Fan or a heater) automatically depending on the temperature difference. The Fan is triggered ON when the room temperature is higher than the set temperature and the heater is triggered ON when the room temperature is lower than the set temperature. The system was designed and simulated using Proteus 8, circuit building software used for building electronics system. Proteus software was used to design and simulate the main circuit, and Micro-C hex file was loaded on the Proteus schematic design. For coding the PIC Microcontroller, Micro-C compiler was used. A 5 V DC power supply was designed in order to provide a biasing voltage to most of the active devices used in the system design circuit. The DC power supply was designed and simulated using Multisim software. The system was simulated and simulation results were in accordance to the design specifications.


24-hour variation in the reactivity of rate-pressure-product to everyday physical activity in patients attending a hypertension clinic.
The exercise-related response of the rate-pressure-product (RPP) is a prognostic marker of autonomic imbalance, cardiovascular mortality, and silent myocardial ischemia in hypertension. In view of the well-known 24 h variation in out-of-hospital sudden cardiac events, our aim was to investigate whether the reactivity of RPP to everyday physical activities varies over the 24 h. Ambulatory measurements of systolic blood pressure (BP) and heart rate were recorded every 20 min for 24 h in 440 diurnally active patients attending a hypertension clinic. Wrist activity counts were summed over the 15 min that preceded a BP measurement. An RPP reactivity index was derived for each of twelve 2 h data bins by regressing the change in RPP against the change in logged activity counts. The RPP showed 24 h variation (p < 0.0005), with a peak of 11,004 (95% CI = 10,757 to 11,250) beat . min(-1) . mmHg occurring at 10:00 h (2 h after mean wake-time). The overall 24 h mean of RPP reactivity was 477 beat . min(-1) . mmHg . logged activity counts(-1) (95% CI = 426 to 529). The largest increase in RPP reactivity occurred within the first 2 h after waking (p < 0.0005). There were no subsequent significant differences in RPP reactivity up to 14 h after waking. The lowest RPP reactivity was found 18-20 h after waking, with a peak-to-trough variation of 593 beat . min(-1) . mmHg . logged activity counts(-1) (95% CI = 394 to 791, p < 0.0005). Although this variation was not moderated by BP status, age, or sex, less variability in RPP reactivity was found for the medicated individuals during the waking hours. These data suggest that under conditions of normal living, the reactivity of RPP to a given change in physical activity increases markedly during the first 2 h after waking from nocturnal sleep, the time when out-of-hospital sudden cardiac events are also most common. Therefore, these data add weight to the notion that reactivity of RPP to physical activity could be a prognostic marker of autonomic imbalance and cardiovascular mortality, although more research is needed to assess the specific prognostic value of 24 h ambulatory measurements of RPP and physical activity.


Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.
Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.


Blast wave loading pathways in heterogeneous material systems-experimental and numerical approaches.
Blast waves generated in the field explosions impinge on the head-brain complex and induce mechanical pressure pulses in the brain resulting in traumatic brain injury. Severity of the brain injury (mild to moderate to severe) is dependent upon the magnitude and duration of the pressure pulse, which in turn depends on the intensity and duration of the oncoming blast wave. A fluid-filled cylinder is idealized to represent the head-brain complex in its simplest form; the cylinder is experimentally subjected to an air blast of Friedlander type, and the temporal variations of cylinder surface pressures and strains and fluid pressures are measured. Based on these measured data and results from computational simulations, the mechanical loading pathways from the external blast to the pressure field in the fluid are identified; it is hypothesized that the net loading at a given material point in the fluid comprises direct transmissive loads and deflection-induced indirect loads. Parametric studies show that the acoustic impedance mismatches between the cylinder and the contained fluid as well as the flexural rigidity of the cylinder determine the shape/intensity of pressure pulses in the fluid.


Gene expression time delays and Turing pattern formation systems.
The incorporation of time delays can greatly affect the behaviour of partial differential equations and dynamical systems. In addition, there is evidence that time delays in gene expression due to transcription and translation play an important role in the dynamics of cellular systems. In this paper, we investigate the effects of incorporating gene expression time delays into a one-dimensional putative reaction diffusion pattern formation mechanism on both stationary domains and domains with spatially uniform exponential growth. While oscillatory behaviour is rare, we find that the time taken to initiate and stabilise patterns increases dramatically as the time delay is increased. In addition, we observe that on rapidly growing domains the time delay can induce a failure of the Turing instability which cannot be predicted by a naive linear analysis of the underlying equations about the homogeneous steady state. The dramatic lag in the induction of patterning, or even its complete absence on occasions, highlights the importance of considering explicit gene expression time delays in models for cellular reaction diffusion patterning.


Ascorbate regulation of 2-Cys peroxiredoxin-A promoter activity is light-dependent.
The 2-Cys peroxiredoxin-A (2CPA) promoter is a model promoter to study redox and ABA-dependent stress signaling. Here, an Arabidopsis reporter gene line expressing luciferase under control of the 2CPA promoter was used to study the impact of ascorbate on reporter gene transcription in a series of protoplast and leaf slice incubation experiments. It was shown that ascorbate has a dual function on gene expression regulation. First, a comparison of responses to ascorbate, dehydroascorbate and reduced and oxidized glutathione demonstrated that ascorbate feeding supports gene expression regulation by increasing the catalytic capacity in redox signaling, as defined by the concentration of low molecular weight antioxidants and their oxidized counterparts. Second, ascorbate had a specific and light-dependent effect on 2CPA transcription, which cannot be substituted by reduced glutathione. Based on the differences between ascorbate and glutathione in the subcellular redox-cycling capacities, it is concluded that ascorbate feeding modulates chloroplast-specific regulation of 2CPA expression.


Heart failure, ischemia/reperfusion injury and cardiac troponin.
Over the forty years since its discovery, there has been a profound transition in thinking with regard to the role of troponin in the control of cardiac function. This transition involved a change in perception oftroponin as a passive molecular switch responding to membrane controlled fluctuations in cytoplasmic Ca2+ to a perception of troponin as a critical element in signaling cascades that actively engage in control of cardiac function. Evidence demonstrating functionally significant developmental and mutant isoform switches and post-translational modifications of cardiac troponin complex proteins, troponin I (cTnI) and troponin T (cTnT) provided convincing evidence for a more complicated role of troponin in control of cardiac function and dynamics. The physiological role of these modifications of troponin is reviewed in this monograph and has also been reviewed elsewhere (Solaro and Rarick, 1998; Gordon et al., 2000; Solaro et al., 2002a; Kobayashi and Solaro, 2005). Our focus here is on studies related to modifications in troponin that appear important in the processes leading from compensated hypertrophy to heart failure. These studies reveal the potentially significant role of post-translational modifications of troponin in these processes. Another focus is on troponin as a target for inotropic agents. Pharmacological manipulation of troponin by small molecules remains an important avenue of approach for the treatment of acute and chronic heart failure (Kass and Solaro, 2006).


Dealing with troubled conscience in municipal care of older people.
Troubled conscience may jeopardize the health of healthcare personnel and, hence, the quality of care provided. Learning more about how personnel deal with their troubled conscience therefore seems important. The aim of this study was to describe personnel's experiences of how they deal with troubled conscience generated in their daily work in municipal care of older people. Interviews were conducted with 20 care providers and analysed with a thematic content analysis. The findings show that in order to deal with troubled conscience, personnel dialogued with themselves and with others. They took measures in a direction they perceived to be correct, and they expressed a need for distancing and re-energizing. It is of importance to share situations that generate troubled conscience in order to find ways to deal with them. Reconsidering one's ways of dealing with troubled conscience may give care providers an opportunity to reach consensus within themselves.


Osteochondral transplantation to treat osteochondral lesions in the elbow.
Effective treatment of osteochondral lesions in the elbow remains challenging. Arthroscopic débridement and microfracture or retrograde drilling techniques are often insufficient and provide only temporary symptomatic relief. The purpose of this study was to evaluate the treatment of these lesions with osteochondral autografts. From 1999 to 2002, seven patients with osteochondral lesions of the capitellum humeri (five patients), trochlea (one patient), or radial head (one patient) were treated with cylindrical osteochondral grafts, which were harvested from the non-weight-bearing area of the proximal aspect of the lateral femoral condyle. The patients (three female and four male patients with an average age of seventeen years) were evaluated preoperatively and postoperatively, with an average follow-up of fifty-nine months. The Broberg and Morrey score was chosen for functional evaluation of the elbow (with regard to motion, pain, strength, activities of daily living, and stability), and the American Shoulder and Elbow Surgeons score was used for the analysis of pain. All patients had imaging studies done preoperatively to evaluate the defect and postoperatively to assess the ingrowth and viability of the graft. The ipsilateral knee was examined for donor-site morbidity. The Broberg and Morrey score improved from a mean (and standard deviation) of 76.3 +/- 13.2 preoperatively to 97.6 +/- 2.7 postoperatively, and pain scores were significantly reduced (p < 0.05). The mean elbow extension lag of 4.7 degrees +/- 5.8 degrees was reduced to 0 degrees postoperatively. Compared with the contralateral side, there was a mean preoperative flexion lag of 12.9 degrees +/- 13.8 degrees . At the time of the final follow-up, flexion was free and was equal bilaterally in all patients. None of the plain radiographs made at the time of follow-up showed any degenerative changes or signs of osteoarthritis. The postoperative magnetic resonance imaging scans showed graft viability and a congruent chondral surface in all seven patients. No donor-site morbidity was noted at one year postoperatively. The osteochondral autograft procedure described in the present study provides the opportunity to retain viable hyaline cartilage for the repair of osteochondral lesions in the elbow while restoring joint congruity and function and perhaps reducing the risk of osteoarthritis. These medium-term results suggest that the risks of a two-joint procedure are modest and justifiable. In addition, the described technique provides an option for revision surgery after the failure of other surgical procedures.


Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate.
Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.


Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI.
Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.


Colors of fruit and vegetables and 10-year incidence of stroke.
The color of the edible portion of fruits and vegetables reflects the presence of pigmented bioactive compounds, (eg, carotenoids, anthocyanidins, and flavonoids). Which fruit and vegetable color groups contribute most to the beneficial association of fruit and vegetables with stroke incidence is unknown. Therefore, we examined associations between consumption of fruit and vegetable color groups with 10-year stroke incidence. This was a prospective, population-based cohort study, including 20,069 men and women age 20 to 65 years and free of cardiovascular diseases at baseline. Participants completed a validated, 178-item food frequency questionnaire. Hazard ratios (HR) were calculated for stroke incidence using multivariate Cox proportional hazards models adjusting for age, sex, lifestyle, and dietary factors. During 10 years of follow-up, 233 incident cases of stroke were documented. Fruits and vegetables were classified into 4 color groups. Medians of green, orange/yellow, red/purple, and white fruit and vegetable consumption were 62, 87, 57, and 118 g/d, respectively. Green, orange/yellow, and red/purple fruits and vegetables were not related to incident stroke. Higher intake of white fruits and vegetables was inversely associated with incident stroke (Q4, >171 g/d, versus Q1, ≤78 g/d; HR, 0.48; 95% CI, 0.29-0.77). Each 25-g/d increase in white fruit and vegetable consumption was associated with a 9% lower risk of stroke (HR, 0.91; 95% CI, 0.85-0.97). Apples and pears were the most commonly consumed white fruit and vegetables (55%). High intake of white fruits and vegetables may protect against stroke.


Healthcare resource utilization and costs among women diagnosed with uterine fibroids compared to women without uterine fibroids.
Objective: To perform a retrospective, matched-cohort, longitudinal evaluation of annual pre- and post-diagnosis costs incurred among women with uterine fibroids (UF) (cases) compared to controls without UF. Methods: Data were derived from the IBM Watson Health MarketScan Commercial Claims and Encounters and Medicaid Multi-State databases. Women aged 18-64 years with ≥1 inpatient or outpatient medical claim with an initial UF diagnosis (index date) from 1 January 2010 to 31 December 2014 were included. Healthcare resource utilization (HCRU) data including pharmacy, outpatient and inpatient hospital claims were collected for 1 year pre-index and ≤5 years post-index. All-cause costs (adjusted to 2017 $US) were compared between cases and controls using multivariable regression models. Results: Analysis included 205,098 (Commercial) and 24,755 (Medicaid) case-control pairs. HCRU and total all-cause healthcare costs were higher for cases versus controls during the pre-index year and all years post-index. Total unadjusted mean all-cause costs were $1197 higher (p < .0001; Commercial) and $2813 higher (standardized difference 0.08; Medicaid) for cases during the pre-index year. Total adjusted mean all-cause costs in the first year post-index were $14,917 for cases versus $5717 for controls in the Commercial population, and $20,244 versus $10,544, respectively, in the Medicaid population. In Years 2-5 post-index, incremental mean adjusted total costs decreased, but remained significantly higher for cases versus controls at all time points in both populations (all p < .05). Conclusions: Costs were higher for women with UF compared to women without UF during the pre-index year and over 5 years post-index; differences were greatest in the first year post-index.


Bone tools from Beds II-IV, Olduvai Gorge, Tanzania, and implications for the origins and evolution of bone technology.
The advent of bone technology in Africa is often associated with behavioral modernity that began sometime in the Middle Stone Age. Yet, small numbers of bone tools are known from Early Pleistocene sites in East and South Africa, complicating our understanding of the evolutionary significance of osseous technologies. These early bone tools vary geographically, with those in South Africa indicating use in foraging activities such as termite extraction and those in East Africa intentionally shaped in a manner similar to lithic tool manufacture, leading some to infer multiple hominin species were responsible for bone technology in these regions, with Paranthropus robustus assumed to be the maker of South African bone tools and Homo erectus responsible for those in East Africa. Here, we present on an assemblage of 52 supposed bone tools primarily from Beds III and IV, Olduvai Gorge, Tanzania, that was excavated by Mary Leakey in the late 1960s and early 1970s, but was only partially published and was never studied in detail from a taphonomic perspective. The majority of the sites from which the tools were recovered were deposited when only H. erectus is known to have existed in the region, potentially allowing a direct link between this fossil hominin and bone technology. Our analysis confirms at least six bone tools in the assemblage, the majority of which are intentionally flaked large mammal bones. However, one of the tools is a preform of the oldest barbed bone point known to exist anywhere in the world and pushes back the initial appearance of this technology by 700 kyr.


Prevalence of bacteria and changes in trends in antimicrobial resistance of Escherichia coli isolated from positive canine urinary samples from an Australian referral hospital over a 5-year period (2013-2017).
Lower urinary tract disease is common in dogs with approximately 14% developing a bacterial lower urinary tract infection (UTI) during their lifetime. Empirical antimicrobials are often prescribed while waiting urine culture and susceptibility results. Regional knowledge of bacterial prevalence and antimicrobial resistance patterns aids veterinarians in antimicrobial choice. This study aimed to identify the prevalence of uropathogens in canine urine tract isolates and to assess for changes in antimicrobial resistance of Escherichia coli (E. coli) over a 5-year study period at a large multidisciplinary private referral hospital in Australia (January 2013-December 2017). The proportion of resistant isolates was compared across 5 years (Fisher's exact test and Cochran Armitage test for trend) for select antimicrobials towards E. coli. A total of 246 positive urine cultures were included. E. coli was the most prevalent uropathogen at 64%, followed by Proteus sp., Staphylococcus sp. and Enterococcus sp., respectively (9%, 8% and 7%). E. coli was most commonly resistant to amoxicillin at 41%. There was no statistically significant difference, nor trend, in resistance of E. coli isolates towards the selected antimicrobials over the 5 years. Resistance towards trimethoprim-sulfonamide was lower at 15%. This information will aid local veterinarians in selecting empirical antimicrobials pending culture results for the treatment of UTIs in dogs.


Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy.
Despite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radio-chemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy x-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 μM MTX and/or 10 μM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV x-rays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER10%). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labelled anti-BrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energy, the shape of the clonogenic survival curve of the pharmacological agents treated cells changes substantially. This change is interpreted as an increased lethality of the local radiation environment and is attributed to supplemented inhibition of DNA repair. Radiation induced chemo-beta therapy was demonstrated in vitro by the targeted activation of combined pharmacological agents with optimized energy tuning of x-ray beams on 9 L cells. Our results show that this is a highly effective form of chemo-radiation therapy.


Transmitting and decoding facial expressions of emotion during healthy aging: More similarities than differences.
Older adults tend to perform more poorly than younger adults on emotional expression identification tasks. The goal of the present study was to test a processing mechanism that might explain these differences in emotion recognition-specifically, age-related variation in the utilization of specific visual cues. Seventeen younger and 17 older adults completed a reverse-correlation emotion categorization task (Bubbles paradigm), consisting of a large number of trials in each of which only part of the visual information used to convey an emotional facial expression was revealed to participants. The task allowed us to pinpoint the visual features each group used systematically to correctly recognize the emotional expressions shown. To address the possibility that faces of different age groups are differently processed by younger and older adults, we included younger, middle-aged, and older adult face models displaying happy, fearful, angry, disgusted, and sad facial expressions. Our results reveal strong similarity in the utilization of visual information by younger and older adult participants in decoding the emotional expressions from faces across ages-particularly for happy and fear emotions. These findings suggest that age-related differences in strategic information use are unlikely to contribute to the decline of facial expression recognition skills observed in later life.


Short bowel syndrome in adults: the need for an interdisciplinary approach and coordinated care.
Short bowel syndrome (SBS) is a heterogeneous disorder with broad variation in disease severity arising from different types of intestinal resection. The spectrum of malabsorption ranges from intestinal insufficiency to intestinal failure. Individualized patient strategies involving modifications of dietary macro- and micronutrients, fluid, and pharmacologic options are required to maximize health and quality-of-life outcomes and to minimize complications and SBS-associated mortality. Intestinal rehabilitation (IR) is an established but evolving approach to improving patient outcomes by decreasing long-term dependency on parenteral support (PS) for nutrition and fluid requirements. Specialized IR programs employ team-based interdisciplinary approaches to coordinate individualized patient care and treatment management through centralized facilities. Such facilities are often specialized intestinal care centers (ICCs) established at large medical centers. A multifaceted IR program offers the comprehensive interrelated services required by patients with SBS-associated intestinal failure throughout the course of disease. Components of interdisciplinary IR programs should include medical services offering diagnostics and monitoring, pharmacologic management, and symptom and complication control; nutrition services, including dietary modifications and interventions; and supportive psychosocial and educational services. A model of care centered on the IR concept means that long-term patient management, including decisions on long-term PS, is overseen by a member of the specialized care center. Rational, seamless, and timely communication among the patient's network of home-based and ICC healthcare providers is crucial to the success of any IR program. This paradigm shift to specialized IR programs will likely result in improvements across the patient care continuum.


When the stress of your environment makes you go HOG wild.
When exposed to increased dissolved solute in their environment (hyperosmotic stress), all eukaryotic cells respond by rapidly activating a conserved mitogen-activated protein kinase cascade, known in budding yeast Saccharomyces cerevisiae as the high osmolarity glycerol (HOG) pathway. Intensive genetic and biochemical analysis in this organism has revealed the presumptive osmosensors, downstream signaling components, and metabolic and transcriptional changes that allow cells to cope with this stressful condition. These findings have had direct application to understanding stress sensing and control of transcription by stress-activated mitogen-activated protein kinases in mammalian cells.


Upper Cervical Surgery, Increased Signal Intensity of the Spinal Cord, and Hypertension as Risk Factors for Dyspnea After Multilevel Anterior Cervical Discectomy and Fusion.
Retrospective study. To investigate the associated risk factors for acute respiratory distress after multilevel anterior cervical discectomy and fusion (ACDF) with a focus on the subjective symptom, dyspnea. Acute respiratory distress after ACDF is a relatively common adverse event, the cause of which is usually soft tissue swelling or hematoma. It can result in serious morbidity and requires careful, focused treatment. We reviewed the records of 532 patients (from January 2014 to August 2018) who had undergone multilevel ACDF surgery. Acute respiratory distress was defined as a complaint of dyspnea within 5 postoperative days. We investigated the patients' demographic parameters, comorbidities, and surgical procedure details. We also investigated radiologic parameters, including magnetic resonance imaging (MRI), with special attention to the prevertebral soft tissue thickness at C3 and C6. Statistical analysis was performed using the Student's t test and multiple logistic regression analysis. Out of a total of 484 patients studied after exclusion criteria were applied, 31 patients (6.6%) experienced dyspnea after surgery. We selected 92 patients from the non-dyspnea group and compared them with 31 patients from the dyspnea group. On univariate analysis, upper cervical surgery involving C3, increased cord signal intensity on T2-weighted imaging (T2WI) magnetic resonance imaging (MRI), hypertension, smoking, and prevertebral soft tissue swelling at C3 level on postoperative day 1 were statistically significant factors associated with dyspnea. On logistic regression analysis, upper cervical surgery involving C3, increased cord signal intensity on T2WI MRI, and hypertension were found to be statistically significant variables (P < 0.05). Patients undergoing upper cervical surgery involving C3, and having increased cord signal intensity on T2WI MRI and hypertension need to be monitored more carefully for acute respiratory distress after multilevel ACDF. 4.


Haplorchis popelkae N. SP. (Digenea: Heterophyidae) from short-necked turtles (Chelidae) in Northern Australia.
Haplorchis popelkae n. sp. is described from the intestine of the short-necked turtles Elseya dentata and Emydura victoriae in Northern Territory, Australia. This slipper-shaped heterophyid digenean differs from the 9 previously known species of Haplorchis in its larger overall size, a forebody that is wider than the hindbody, comparatively short ceca, and a ventral sucker that is less heavily spined than in many other species in the genus. This is the first report of Haplorchis in turtles.


Towards optimised drug delivery: structure and composition of testosterone enanthate in sodium dodecyl sulfate monolayers.
Surface tension and specular neutron reflectivity measurements have been used, for the first time to systematically study both the interfacial structure and composition of monolayers of the soluble surfactant, sodium dodecyl sulfate containing a low-dose, poorly water soluble drug, testosterone enanthate. Modelling of the specular neutron reflectivity data suggests that the hydrophobic testosterone enanthate was adsorbed in the C12 hydrophobic tail region of the surfactant monolayer, regardless of the concentration of surfactant at the interface and whether or not additional drug was added to the interface. The location of the hydrophobic drug in the tail region of the surfactant monolayer is supported by the results of classical, large-scale molecular dynamics simulations. The thickness of the surfactant monolayer obtained, in the presence and absence of drug, using molecular dynamics simulations was in good agreement with the corresponding values obtained from the specular neutron reflectivity measurements. The stoichiometry of surfactant:drug at the air-water interface at sodium dodecyl sulfate concentrations above the critical micelle concentration was determined from specular neutron reflectivity measurements to be approximately 3 : 1, and remained constant after the spreading of further testosterone enanthate at the interface. Significantly, this stoichiometry was the same as that obtained in the micelles from bulk solubilisation studies. Important insights into the preferred location of drug in surfactant monolayers at the air-water interface as well as its effect on the structure of the monolayer have been obtained from our combined use of experimental and simulation techniques.