Differences in legal characteristics between Caucasian and African-American women diverted into substance abuse treatment.
In this exploratory study, we examined differences in the legal characteristics of Caucasian and African-American female offenders (n = 122) who were diverted into substance abuse treatment, to identify any racial disparities. We also examined the differences between groups in demographics and in substance abuse, family, and violence histories. In terms of legal characteristics, the results showed that African-American female offenders were significantly more likely to have been incarcerated at the time of their substance dependency evaluation than were Caucasian female offenders. Also, African-American women were more likely to have served 13 months for the current legal charge in comparison to the 4 months served by Caucasian women, although no differences were found between groups in the severity of the current legal charge. Comparison of demographics and substance abuse, family, and violence histories indicated that African-American women were more likely to be undereducated, crack cocaine dependent, and overly exposed to violence. Overall, the sample of female offenders evidenced severe substance dependency problems, a strong need for inpatient substance abuse treatment, and chronic legal and social difficulties. Implications of these findings are discussed in relation to unbalanced sentencing policies and increasing awareness of the treatment needs of this unique population.


Evolution of Mating Systems in Basidiomycetes and the Genetic Architecture Underlying Mating-Type Determination in the Yeast Leucosporidium scottii.
In most fungi, sexual reproduction is bipolar; that is, two alternate sets of genes at a single mating-type (MAT) locus determine two mating types. However, in the Basidiomycota, a unique (tetrapolar) reproductive system emerged in which sexual identity is governed by two unlinked MAT loci, each of which controls independent mechanisms of self/nonself recognition. Tetrapolar-to-bipolar transitions have occurred on multiple occasions in the Basidiomycota, resulting, for example, from linkage of the two MAT loci into a single inheritable unit. Nevertheless, owing to the scarcity of molecular data regarding tetrapolar systems in the earliest-branching lineage of the Basidiomycota (subphylum Pucciniomycotina), it is presently unclear if the last common ancestor was tetrapolar or bipolar. Here, we address this question, by investigating the mating system of the Pucciniomycotina yeast Leucosporidium scottii. Using whole-genome sequencing and chromoblot analysis, we discovered that sexual reproduction is governed by two physically unlinked gene clusters: a multiallelic homeodomain (HD) locus and a pheromone/receptor (P/R) locus that is biallelic, thereby dismissing the existence of a third P/R allele as proposed earlier. Allele distribution of both MAT genes in natural populations showed that the two loci were in strong linkage disequilibrium, but independent assortment of MAT alleles was observed in the meiotic progeny of a test cross. The sexual cycle produces fertile progeny with similar proportions of the four mating types, but approximately 2/3 of the progeny was found to be nonhaploid. Our study adds to others in reinforcing tetrapolarity as the ancestral state of all basidiomycetes.


Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice.
The present study tested whether individual differences in anxiety- and fear-related behaviour are associated with between-subjects variation in postmortem brain levels of selected neurotrophic factors. Naïve C57BL6/J mice of both sexes were subjected either to an elevated plus maze test or to a Pavlovian fear conditioning paradigm. Two days after behavioural assays, the mice were sacrificed for postmortem quantification of the protein levels of brain derived neurotrophic factors (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) in the hippocampus and amygdala. Significant correlations between behavioural measures and postmortem regional neurotrophic factor contents were revealed. The magnitude of anxiety-like behaviour in the elevated plus maze was positively related to dorsal hippocampal BDNF levels, but negatively related to NGF levels in dorsal hippocampus and in the amygdala. On the other hand, the expression of conditioned fear is positively related to amygdala BDNF and NGF levels, and to dorsal hippocampal NGF levels. Our results add to existing reports in human as well as in animals of correlation between anxiety trait and gross measures of hippocampal volume or activation levels. Moreover, a distinction between spontaneous and learned (or conditioned) anxiety/fear would be relevant to the identification of neurotrophin signalling mechanisms in the hippocampus and amygdala implicated in anxiety and related psychopathology.


Plasma urocortin in human systolic heart failure.
Urocortin (UCN), a member of the corticotrophin-releasing factor family, is expressed in heart, brain and gut. UCN has potent cardiostimulatory, cardioprotective, vasodilator and diuretic/natriuretic effects, and cardiac UCN expression is increased in heart failure (HF). In the present study, we investigated plasma levels of UCN in 119 patients with HF and 212 age- and gender-matched controls to clarify its relationship with gender and disease severity. UCN was elevated in HF [normal males, 19.5 (3.9-68.8) pmol/l and HF males, 50.2 (6.9-108.2) pmol/l, P < 0.0005; normal females, 14.2 (3.9-53.5) pmol/l and HF females, 21.8 (3.9-112.5) pmol/l, P < 0.001; values are medians (range)]. The relative increase was greater in males than females ( P < 0.03). UCN fell with increasing age, especially in HF patients ( r(s) = -0.56, P < 0.0005) and with increasing New York Heart Association (NYHA) class ( r(s) = -0.55, P < 0.0005). The fall in UCN levels with increasing NYHA class was reinforced by a significant correlation between UCN and ejection fraction ( r(s) = 0.45, P < 0.0005) in HF patients. Although receiver operating characteristic (ROC) curves for diagnosis of all HF cases yielded an area under the curve (AUC) of 0.76, ROC AUCs for patients with early HF (NYHA class I and II) were better (0.91). ROC AUCs for logistic models incorporating N-terminal probrain natriuretic peptide (N-BNP) and UCN were better than either peptide alone. In conclusion, plasma UCN is elevated in HF, especially in its early stages. Its decline with increasing HF severity may expedite disease progression due to diminished cardioprotective/anti-inflammatory effects. UCN measurement may also complement N-BNP in the diagnosis of early HF.


Transcriptional regulation of pattern recognition receptors by Jak/STAT signaling, and the implications for disease pathogenesis.
Cytokines are well known for their pleiotropism, affecting a large number of cellular responses, including proliferation, survival, functional maturation, and immunomodulation. It is, therefore, not surprising that both the deregulated expression of cytokines and the subsequent activation of their downstream signaling pathways is a common feature of many cancers, as well as chronic inflammatory, autoimmune, metabolic, and cardiovascular diseases. In this regard, activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is the predominant intracellular signaling event triggered by cytokines, with STAT1 and STAT3 having the greatest diversity of biological functions among the 7 known members of the STAT family of latent transcription factors. Notably, over recent years, it has emerged that STAT1 and STAT3 are employed by various cytokines to manipulate the signal output of heterologous receptors of the innate immune system, namely pattern recognition receptors (PRRs), with both immune and nonimmune (eg, oncogenic, metabolic) cellular processes being affected. This review highlights these pivotal advancements in our understanding of how a cross talk between cytokine and PRR signaling networks can impact on a variety of cellular responses during disease pathogenesis, and the potential therapeutic implications of targeting these networks.


Aerosol-OT in water forms fully-branched cylindrical direct micelles in the presence of the ionic liquid 1-butyl-3-methylimidazolium bromide.
A recent investigation on the sodium bis(2-ethylhexyl)sulfosuccinate/water/1-butyl-3-methylimidazolium tetrafluoborate (NaAOT/W/bmimBF(4)) system showed that the anionic two-tailed surfactant NaAOT, that is known to form reverse micelles or planar interfaces (typically lamellar liquid crystals), can originate discrete spherical micelles of normal curvature because of strong interactions with the ionic liquid. The goal of the present paper was to detect macro- and microscopic modifications within such a system upon substitution of the ionic liquid's counter-ion tetrafluoroborate with bromide. Firstly, the phase diagram of the NaAOT/water/bmimBr system was determined. Then, the monophasic regions were investigated by means of NMR self-diffusion and SAXRD experiments. The results obtained proved this system to be surprisingly different from that containing bmimBF(4). This study focused mainly on the characterization of the micellar region, which turned out to be constituted of a bicontinuous nanostructure. This finding can be accounted for suggesting a decreasing of the NaAOT effective surfactant packing parameter, as in the case of NaAOT/water/bmimBF(4) system, although the effect in the presence of Br(-) is less pronounced. Data modeling showed the same degree of interfacial adsorption for the bmim(+) cation in both systems, regardless of the particular counterion used-either BF(4)(-) or Br(-). Thus, the remarkable differences between the two systems appear to be mainly due to a specific counterion effect. This result highlights once again the ions specificity, which is found ubiquitously in chemistry and biology.


Heparin and graduated compression stockings in patients undergoing fractured hip surgery.
Despite evidence that effective regimens are available for the prevention of venous thrombosis in fractured hip patients, many centers do not use prophylaxis. In order to evaluate the efficacy and safety of heparin and graduated compression stockings, we conducted a cohort study of 55 consecutive fractures hip patients treated postoperatively with heparin, 5,000 U every 12 h, and graduated compression stockings. The rates of venous thromboembolism and bleeding were compared with an historical cohort from Hamilton. Before discharge, 51 patients underwent bilateral venography. Deep venous thrombosis (DVT) occurred in 10 of the 51 patients (incidence of 20%); three had proximal DVT (incidence of proximal DVT was 6%). DVT was seen in 29 of the 63 control patients (incidence 46%); 19 had proximal DVT (incidence of proximal DVT was 30%). The differences in the rates of DVT and proximal DVT are statistically significant (p less than 0.01). Bleeding occurred in one patient in the treatment group (incidence 2%) and five patients in the control group (incidence 8%). This study confirms that therapy with heparin and graduated compression stockings is effective, inexpensive, and convenient for the prevention of venous thrombosis in fractured hip patients and is associated with a low bleeding risk.


Is phenytoin a safe agent for staple line recovery after gastric sleeve surgery in rats?
The most challenging and mortal complication of gastric sleeve surgery (SG) is staple line leakage. Although many agents have been used for increasing tissue healing on the stapler line, there is still no consensus on its effectiveness and efficacy. The aim of study is to determine the effect of phenytoin on the healing process of gastric sleeve surgery in rats. On the 10th post-operative day, the effects of phenytoin on bursting pressure in the stapler line were evaluated along-side pathohistological examinations. To investigate the molecular impact of phenytoin on the expression of TGF-β, VEGF, FGF2, and p53 genes, quantitative real-time polymerase chain reaction was utilized. In addition, gene expressions at the protein level were deter-mined by immunohistochemical analysis. No signs of intra-abdominal leakage were observed in the resected samples. A statistically essential extend in stable line bursting pressure measure was observed between the control group and the group treated with phenytoin application. Pathohisto-logical results indicate that the mean score of collagens of the study group (3.2±0.42) was significantly higher than the control group (2.3±0.48) (P=0.003). In addition, the mean epithelization score of the study group (3.4±0.52) was significantly higher than the control group (2.1±0.57) (P=0.001). mRNA of TGFβ, FGF2, VEGF, and p53 genes drastically increased phenytoin treated group. High FGF2 protein expression levels were determined from phenytoin use compared to the control group. Molecular studies suggest that phenytoin may increase the healing process of Gastric sleeve following SG in rats and may become a new agent for the prevention of human gastric leaks.


Parkinsonsim due to a Chronic Subdural Hematoma.
Subdural hematoma is a rare cause of parkinsonism. We present the case of a 78-year-old man with right-side dominant parkinsonism about 3 months after a minor head injury. MRI reveals a chronic subdural hematoma on the left side with mildly displaced midline structures. The parkinsonian features were almost completely disappeared after neurosurgical evacuation of the hematoma without any anti-parkinson drug.


Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway.
Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEK-Nup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-κB signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-κB-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IκB, in the nucleus. These results suggest that SET-Nup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system.


Sugar interaction with metals in aqueous solution: indirect determination from infrared and direct determination from nuclear magnetic resonance spectroscopy.
In this article, mid-infrared Fourier transform (Mid-FT-IR) and carbon thirteen nuclear magnetic resonance (13C NMR) spectroscopy have been used to determine possible interactions between sucrose and various alkali or alkaline earth metals in aqueous solution. In the presence of these metals, significant shifts in the absorption bands of sucrose were noted by mid-FT-IR coupled with principal component analysis (PCA). These shifts were explained on the basis of weakening of the H-bond network between sucrose and water and possible interactions between sucrose and the metal ion. Factorial maps were established and the spectral patterns obtained show that these interactions vary according to the nature of the metal ion. 13C NMR analysis showed that the carbon atoms of sucrose undergo shielding or deshielding in the presence of metal ions in aqueous solutions. Two factors were invoked to account for the variation of chemical shifts: the rupture of hydrogen bonds due to hydration of the metal ion and the possible coordination of the metal ion to the oxygen atoms of sucrose.


Sample Size Requirements for Discrete-Choice Experiments in Healthcare: a Practical Guide.
Discrete-choice experiments (DCEs) have become a commonly used instrument in health economics and patient-preference analysis, addressing a wide range of policy questions. An important question when setting up a DCE is the size of the sample needed to answer the research question of interest. Although theory exists as to the calculation of sample size requirements for stated choice data, it does not address the issue of minimum sample size requirements in terms of the statistical power of hypothesis tests on the estimated coefficients. The purpose of this paper is threefold: (1) to provide insight into whether and how researchers have dealt with sample size calculations for healthcare-related DCE studies; (2) to introduce and explain the required sample size for parameter estimates in DCEs; and (3) to provide a step-by-step guide for the calculation of the minimum sample size requirements for DCEs in health care.


Racial and ethnic disparities in prenatal syphilis screening among women with Medicaid-covered deliveries in Florida.
Black and Hispanic infants are 19.9 and 10.3 times more likely, respectively, than white infants to develop congenital syphilis (CS), a disease that is preventable with timely prenatal screening and treatment. We examined racial/ethnic group differences in prenatal syphilis screening among pregnant women with equal financial access to prenatal care through Medicaid. We used Florida claims data to examine any, early, and repeat screening among non-Hispanic white, non-Hispanic black, and Hispanic women with Medicaid-covered deliveries in FY1995 (n=56,088) and FY2000 (n=54,073). We estimated screening rates for each group, and used logistic regression to assess whether screening disparities remained after controlling for other factors, including Medicaid enrollment characteristics and prenatal care source, and associations between access-related factors and screening odds for each group. Between FY1995 and FY2000, rates of any and early syphilis screening increased, while repeat screening rates decreased. In FY1995, any, early, and repeat rates were highest for blacks and lowest for Hispanics. In FY2000, any and early screening rates were highest for whites and lowest for blacks, while repeat screening rates were similar across groups. Racial/ethnic differences in any and early screening remained for non-Hispanic blacks after adjustment. In general, Medicaid enrollment early in pregnancy, primary care case management participation, and use of a safety net clinic were associated with higher screening odds, though results varied by test type and across groups. Unexplained racial/ethnic disparities in prenatal syphilis screening remain for blacks, but not Hispanics. Individual, provider, and program factors contribute to differences across and within groups.


Suppression of sympathetic ganglionic neurotransmission by the selective dopamine-1 receptor agonist fenoldopam (SK&F 82526) in the anesthetized dog.
This study was designed to determine the role of dopamine (DA) receptors in modulation of sympathetic ganglionic neurotransmission utilizing the selective DA-1 agonist fenoldopam. Preganglionic stimulation of cardiac sympathetic nerves (0.5-2.0 Hz), in pentobarbital anesthetized dogs, resulted in frequency-dependent tachycardia. Fenoldopam (10 and 30 micrograms/kg/min i.v.) suppressed the tachycardic response 45% at 0.5 Hz with no significant effect at higher stimulation frequencies. In the presence of SK&F 83566 (10 micrograms/kg/min i.v.), a selective DA-1 receptor antagonist, fenoldopam no longer elicited significant inhibition of the preganglionic response. When postganglionic cardiac nerves were stimulated (0.5 Hz), fenoldopam (100 micrograms/kg/min i.v.) inhibited the response 55% with no significant effect at lower doses. Stimulation of sympathetic preganglionic fibers in the autoperfused hindlimb of the dog induced vasoconstriction. Fenoldopam (3 micrograms/kg/min i.a.) produced marked inhibition of nerve-induced constriction that was partially antagonized by SK&F 83566 (3 micrograms/kg/min i.a.). Complete inhibition of the effect of fenoldopam on sympathetic nerve stimulation in the hindlimb could not be achieved, as a component of this action was apparently due to postjunctional alpha-2 adrenoceptor blockade. This was evidenced by a reduction in the pressor response to the selective alpha-2 adrenoceptor agonist B-HT 920 by fenoldopam. These data indicate that fenoldopam stimulates DA-1 receptors in sympathetic ganglia to inhibit neurotransmission and this effect can be reversed by a selective DA-1 receptor antagonist.


IVIg in idiopathic autoimmune neuropathies: analysis in the light of the latest results.
High-dose intravenous immunoglobulin (IVIg) is effective in the treatment of idiopathic autoimmune neuropathies including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN), representing a useful option or, as in MMN, the gold standard for their treatment. In GBS, two randomised, controlled trials (RCT) showed that IVIg is at least as effective as plasma exchange (PE). IVIg may however be preferred due to its low number of contraindications and complications and the fact that it can be administered at any time, in any department, including patients with contraindications to PE, or in intensive care units. In CIDP, at least four RCTs have demonstrated the efficacy of IVIg in over 60% of CIDP patients, while two additional RCTs have shown a comparable effect to steroids and PE as initial treatment. As with PE, the effects of IVIg usually last a few weeks meaning that the majority of patients require periodic maintenance infusions. The lower cost and easier administration of oral steroids compared to IVIg may be partly compensated by the safer long-term profile of IVIg over steroids. In MMN, almost 80% of patients improve with IVIg, the efficacy of which has been confirmed by four RCTs, making of IVIg the first-choice therapy in MMN, for which steroids and PE are ineffective or even detrimental. Also in these patients, IVIg induces a rapid improvement that usually lasts only a few weeks and has to be maintained with periodic IVIg infusions for long periods of time, if not indefinitely.


Melissa officinalis L. decoctions as functional beverages: a bioactive approach and chemical characterization.
Lemon balm (Melissa officinalis L.) is a member of the Lamiaceae family with a long story of human consumption. It has been consumed for decades, directly in food and as a decoction or an infusion for its medicinal purposes. In this manuscript, a detailed chemical characterization of the decoction of this plant is described, encompassing antimicrobial, antioxidant and antitumor activities. Rosmarinic acid and lithospermic acid A were the most abundant phenolic compounds. Quinic acid, fructose, glucose and γ-tocopherol were the most abundant within their groups of molecules. M. officinalis decoctions were active against a wide range of microorganisms, Pseudomonas aeruginosa and Salmonella typhimurium, and Penicillium funiculosum being the most sensitive bacteria and fungi, respectively. The growth inhibition of different human tumor cell lines (mainly MCF-7 and HepG2) was also observed, as also high free radical scavenging activity and reducing power. This manuscript highlights some beneficial effects of these functional beverages.


Microautophagy: lesser-known self-eating.
Microautophagy, the non-selective lysosomal degradative process, involves direct engulfment of cytoplasmic cargo at a boundary membrane by autophagic tubes, which mediate both invagination and vesicle scission into the lumen. With its constitutive characteristics, microautophagy of soluble substrates can be induced by nitrogen starvation or rapamycin via regulatory signaling complex pathways. The maintenance of organellar size, membrane homeostasis, and cell survival under nitrogen restriction are the main functions of microautophagy. In addition, microautophagy is coordinated with and complements macroautophagy, chaperone-mediated autophagy, and other self-eating pathways. Three forms of selective microautophagy, including micropexophagy, piecemeal microautophagy of the nucleus, and micromitophagy, share common ground with microautophagy to some degree. As the accumulation of experimental data, the precise mechanisms that govern microautophagy are becoming more appreciated. Here, we review the microautophagic molecular machinery, its physiological functions, and relevance to human diseases, especially in diseases involving multivesicular bodies and multivesicular lysosomes.


Control of Multilevel Resistance in Vanadium Dioxide by Electric Field Using Hybrid Dielectrics.
We investigate the effect of electric field on VO2 back-gated field effect transistor (FET) devices. Using hybrid dielectric layers, we demonstrate the highest resistance modulation on the order of 102 in VO2 at a positive gate bias of 80 V (1.6 MV/cm). VO2 FET devices are prepared on SiO2 substrates of different thicknesses (100-300 nm) and hybrid dielectric layers of Al2O3/SiO2 (500 nm). For thicknesses less than 300 nm, no electric-field effects are observed, whereas for a 300 nm thickness, a small decrease in resistance is observed under a 0.2 MV/cm electric field. Under the electrostatic effect, the carrier concentration increases in VO2 devices, decreasing the resistance and the transition temperature from 66.75 to 64 °C. The leakage analysis shows that the interface quality of VO2 films on hybrid dielectric layers can be further improved. These studies suggest a multilevel fast resistance switching with the electric field and give an insight into the gate-source leakage current, which limits the phase transition in VO2 in an electric field.


Long-term follow-up of cognitive outcome after breech presentation at birth.
Studies of long-term consequences of birth in breech presentation are sparse. Therefore, we conducted a cohort study linking birth registry data with data collected during evaluation for military service in 4,298 conscripts born between 1973 and 1976. The cognitive functions were measured with the Boerge Prien IQ test. A total of 164 conscripts were born in breech presentation and 70 (42.7%) of these were delivered after Caesarean section. The mean Boerge Prien test score was 43.2 among men born in cephalic presentation and 39.9 among those born in breech presentation for a difference of 3.3 (95% confidence interval = 1.8-4.7). The negative association between breech presentation and cognitive outcome persisted after stratifying by Caesarean section and after adjustment for confounders. It also persisted when we restricted the analyses to term singleton pregnancies.


A Mechanistic Model of the Intravitreal Pharmacokinetics of Large Molecules and the Pharmacodynamic Suppression of Ocular Vascular Endothelial Growth Factor Levels by Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration.
Intravitreal injection of anti-VEGF (vascular endothelial growth factor) antibodies or antibody fragments has been shown to be a highly effective treatment for neovascular age-related macular degeneration (wet AMD). The ocular half-life (t1/2) of these large molecules, determined in ocular fluids or derived from serum levels, varies with molecular size and is larger in humans than in preclinical animal species. The high affinity binding of VEGF to these molecules lowers the free concentration of VEGF and reduces its occupancy on VEGF receptors in ocular tissues. To understand the biophysical determinants of t1/2 for anti-VEGF antibodies and the time-course of VEGF in ocular fluids, we developed a mechanistic model of intravitreal pharmacokinetics (IVT PK) for anti-VEGF antibodies and combined it with a mechanistic model of the pharmacodynamics (RVR PD) of VEGF suppression by ranibizumab, an anti-VEGF recombinant, humanized monoclonal antibody fragment (Fab). Our IVT PK model predicts that the ocular t1/2 of a large molecule will be approximately four-times the calculated value of its vitreous diffusion time (Tdiff), defined as rvit(2)/6D, where rvit is the radius of the vitreous chamber in that species (modeled as a sphere), and D is the diffusion coefficient of the molecule in physiological saline at 37 °C obtained from the Stokes-Einstein relation. This prediction is verified from a compilation of data and calculations on various large molecules in the human, monkey, rabbit, and rat and is consistent with the reported t1/2 values of ranibizumab in humans (mean value 7.9 days) and the calculated Tdiff of 1.59 days. Our RVR PD model is based on the publication of Saunders et al. (Br. J. Ophthalmol. 2015, 99, 1554-1559) who reported data on the time-course of VEGF levels in aqueous humor samples obtained from 31 patients receiving ranibizumab treatment for wet AMD and developed a compartmental mathematical model to describe the VEGF suppression profiles. We modified Saunders' model with the known 2:1 stoichiometry of ranibizumab-VEGF binding and included the association and dissociation kinetics of the binding reactions. Using the RVR PD model, we reanalyzed Saunders' data to estimate the in vivo dissociation constant (KD) between ranibizumab and VEGF. Our analysis demonstrates the delicate interrelationship between the in vivo KD value and the intravitreal half-life and yields an in vivo KD estimate that is appreciably larger than the in vitro KD estimates reported in the literature. Potential explanations for the difference between the in vivo and in vitro KD values, which appear to reflect the different methodologies and experimental conditions, are discussed. We conclude that the combined mechanistic model of IVT PK and RVR PD provides a useful framework for simulating the effects of dose, KD, and the molecular weight of VEGF-binding molecules on the duration of VEGF suppression.


Provider perceptions and expectations of breast cancer posttreatment care: a University of California Athena Breast Health Network project.
The Athena Breast Health Network collaboration is a University of California system-wide project initiated with the intent to drive innovation in breast cancer prevention, screening, and treatment. This qualitative research examines provider perceptions and expectations of posttreatment breast cancer care across five network sites with the goal of better understanding provider behavior during the posttreatment phase of the cancer care trajectory. Investigators at each site conducted semi-structured interviews with oncology specialists and primary care providers (PCPs). Interviews used case study examples and open- and closed-ended questions on the delivery of posttreatment breast cancer care. Informant responses were manually recorded by the interviewer, compiled in a database, then coded and analyzed using NVivo 9 software. There were 39 key informants across the sites: 14 medical oncologists, 7 radiation oncologists, 11 surgeons, 3 oncology nurses, and 4 PCPs. Care coordination was a major unprompted theme identified in the interviews. There was a perceived need for greater care coordination across institutions in order to improve delivery of posttreatment health care services and a need for greater care coordination within oncology, particularly to help avoid duplication of follow-up care and services. Participants expect frequent follow-up visits and to use biomarker tests and advanced imaging services as part of routine surveillance care. Implementing survivorship care programs was perceived as a way to improve care delivery. These results identify a need for increased focus on care coordination during the posttreatment phase of breast cancer care within the University of California system and the potential for system and provider-level interventions that could help increase coordination of posttreatment care. Breast cancer survivors do not always receive evidence-based care. This research helps to better understand what motivates provider behavior during the posttreatment phase and lays a foundation for targeted interventions to increase adherence to evidence-based recommendations.


A versatile ultra high vacuum sample stage with six degrees of freedom.
We describe the design and practical realization of a versatile sample stage with six degrees of freedom. The stage was designed for use in a Low Energy Electron Microscope, but its basic design features will be useful for numerous other applications. The degrees of freedom are X, Y, and Z, two tilts, and azimuth. All motions are actuated in an ultrahigh vacuum base pressure environment by piezoelectric transducers with integrated position sensors. The sample can be load-locked. During observation, the sample is held at a potential of -15 kV, at temperatures between room temperature and 1500 °C, and in background gas pressures up to 1 × 10(-4) Torr.


Pandemic influenza in Australia: using telephone surveys to measure perceptions of threat and willingness to comply.
Baseline data is necessary for monitoring how a population perceives the threat of pandemic influenza, and perceives how it would behave in the event of pandemic influenza. Our aim was to develop a module of questions for use in telephone health surveys on perceptions of threat of pandemic influenza, and on preparedness to comply with specific public health behaviours in the event of pandemic influenza. A module of questions was developed and field tested on 192 adults using the New South Wales Department of Health's in-house Computer Assisted Telephone Interviewing (CATI) facility. The questions were then modified and re field tested on 202 adults. The module was then incorporated into the New South Wales Population Health Survey in the first quarter of 2007. A representative sample of 2,081 adults completed the module. Their responses were weighted against the state population. The reliability of the questions was acceptable with kappa ranging between 0.25 and 0.51. Overall 14.9% of the state population thought pandemic influenza was very or extremely likely to occur; 45.5% were very or extremely concerned that they or their family would be affected by pandemic influenza if it occurred; and 23.8% had made some level of change to the way they live their life because of the possibility of pandemic influenza. In the event of pandemic influenza, the majority of the population were willing to: be vaccinated (75.4%), be isolated (70.2%), and wear a face mask (59.9%). People with higher levels of threat perception are significantly more likely to be willing to comply with specific public health behaviours. While only 14.9% of the state population thought pandemic influenza was very or extremely likely to occur, a significantly higher proportion were concerned for self and family should a pandemic actually occur. The baseline data collected in this survey will be useful for monitoring changes over time in the population's perceptions of threat, and preparedness to comply with specific public health behaviours.


Multiple correlative immunolabeling for light and electron microscopy using fluorophores and colloidal metal particles.
Multiple correlative immunolabeling permits colocalization of molecular species for sequential observation of the same sample in light microscopy (LM) and electron microscopy (EM). This technique allows rapid evaluation of labeling via LM, prior to subsequent time-consuming preparation and observation with transmission electric microscopy (TEM). The procedure also yields two different complementary data sets. In LM, different fluorophores are distinguished by their respective excitation and emission wavelengths. In EM, colloidal metal nanoparticles of different elemental composition can be differentiated and mapped by energy-filtering transmission electron microscopy with electron spectroscopic imaging. For the highest level of spatial resolution in TEM, colloidal metal particles were conjugated directly to primary antibodies. For LM, fluorophores were conjugated to secondary antibodies, which did not affect the spatial resolution attainable by fluorescence microscopy but placed the fluorophore at a sufficient distance from the metal particle to limit quenching of the fluorescence signal. It also effectively kept the fluorophore at a sufficient distance from the colloidal metal particles, which resulted in limiting quenching of the fluorescent signal. Two well-defined model systems consisting of myosin and alpha-actinin bands of skeletal muscle tissue and also actin and alpha-actinin of human platelets in ultrathin Epon sections were labeled using both fluorophores (Cy2 and Cy3) as markers for LM and equally sized colloidal gold (cAu) and colloidal palladium (cPd) particles as reporters for TEM. Each sample was labeled by a mixture of conjugates or labels and observed by LM, then further processed for TEM.


Quantification of infectious duck hepatitis B virus by radioimmunofocus assay.
A simple method is described for the precise quantification of infectious duck hepatitis B virus (DHBV) in cell culture, using a radioimmunofocus assay (RIFA). Primary duck hepatocyte cell cultures were infected with serial dilutions of viral samples as for a plaque assay, but then maintained with liquid overlay medium. After incubation for up to 14 days, cell monolayers were fixed with acetone, then stained with a monoclonal antibody to DHBV L protein followed by secondary antibody labelled with 125I. Foci of infection (representing individual infectious particles in the inoculum) were detected by autoradiography. The number of foci recovered was increased by addition of dimethyl sulphoxide to culture medium, but was not appreciably altered by the use of semi-solid medium. The titre of virus suspensions determined by RIFA correlated well with titration in ducklings. The RIFA is a useful method for titration of DHBV, as it has a wide dynamic range and is well suited to parallel titration of large numbers of samples. This assay will have wide use for the analysis of DHBV growth kinetics, antiviral efficacy, and virus inactivation procedures.


QTL mapping for aluminum tolerance in RIL population of soybean (Glycine max L.) by RAD sequencing.
Aluminum (Al3+) toxicity is a typical abiotic stress that severely limits crop production in acidic soils. In this study, an RIL (recombinant inbred line, F12) population derived from the cross of Zhonghuang 24 (ZH 24) and Huaxia 3 (HX 3) (160 lines) was tested using hydroponic cultivation. Relative root elongation (RRE) and apical Al3+ content (AAC) were evaluated for each line, and a significant negative correlation was detected between the two indicators. Based on a high-density genetic linkage map, the phenotypic data were used to identify quantitative trait loci (QTLs) associated with these traits. With composite interval mapping (CIM) of the linkage map, five QTLs that explained 39.65% of RRE and AAC variation were detected on chromosomes (Chrs) Gm04, Gm16, Gm17 and Gm19. Two new QTLs, qRRE_04 and qAAC_04, were located on the same region of bin93-bin94 on Chr Gm04, which explained 7.09% and 8.98% phenotypic variation, respectively. Furthermore, the results of the expression analysis of candidate genes in the five genetic regions of the QTLs showed that six genes (Glyma.04g218700, Glyma.04g212800, Glyma.04g213300, Glyma.04g217400, Glyma.04g216100 and Glyma.04g220600) exhibited significant differential expression between the Al3+ treatment and the control of two parents. The results of qRT-PCR analysis indicated that Glyma.04g218700 was upregulated by Al3+ treatment with the hundreds-fold increased expression level and may be a candidate gene with potential roles in the response to aluminum stress. Therefore, our efforts will enable future functional analysis of candidate genes and will contribute to the strategies for improvement of aluminum tolerance in soybean.


[Clinical and cost effectiveness of rehabilitation programs including physical exercises for patients with ischemic heart disease under conditions of resort and outpatient clinics].
The objective of the present study was to evaluate clinical and cost effectiveness of rehabilitation programs including long-term physical training of moderate intensity intended for the management of patients with coronary heart disease (CHD) who had undergone acute coronary events; the programs were adapted to the treatment under conditions of spa resorts, dispensaries, and outpatient clinics. It was shown that rehabilitation of patients presenting with CDH with the use of moderately intensive physical exercises during a long period enhances the effectiveness of application of the available funds due to improved clinical course of coronary heart disease, tolerance of physical load, and quality of life.


Associations between race, lifecourse socioeconomic position and prevalence of diabetes among US women and men: results from a population-based panel study.
Few studies have examined the degree to which racial disparities in the development of diabetes are accounted by differences in lifecourse socioeconomic position (SEP). We assessed the association between race, lifecourse SEP measures and prevalence of diabetes in a representative US sample of black and white adults. A generalised estimating equations approach was used with a sample of 3497 adults from the Americans' Changing Lives study. Sex-specific models were calculated to compute prevalence ratios (PR) for associations of race and SEP with self-reported diagnoses of diabetes. For men, childhood and adult SEP were unrelated to diabetes, and adjustment for lifecourse SEP had little effect on the excess diabetes in blacks (PR=1.56, 95% CI 1.11 to 2.21). Adjustment for measures of lifecourse SEP reduced the PR for the association between race and diabetes in women from 1.96 (95% CI 1.52 to 2.54) to 1.40 (95% CI 1.04 to 1.87) with the respondent's education responsible for most of the reduction in the association. However, diabetes was also inversely associated with father's education, and low SEP throughout the lifecourse was associated with a nearly threefold increase in diabetes (PR=2.89, 95% CI 2.10 to 3.99). Racial disparities in diabetes existed among both men and women, but lifecourse SEP was related to diabetes only among women. The pathway and cumulative hypotheses for lifecourse SEP effects on diabetes may be especially salient for women.


Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with (90)Y microspheres: the experience of the National Tumor Institute of Milan.
In most centres, the choice of the optimal activity to be administered in selective intra-arterial radioembolization with microspheres is nowadays based on empirical models which do not take into account the evaluation of tumour and non tumour individual absorbed dose, despite plenty of published data which showed that local efficacy is correlated to tumour absorbed dose, and that the mean absorbed dose is a toxicity risk factor. A pitfall of the crudest, empirical tumour involvement method are 20 deaths in a single centre which adopted it to administer the whole liver, or the need of systematic 25% subjective reduction of activity prescribed with body surface area method. In order to develop a possibly safer and more effective strategy based on real individual dosimetry, we examine first external beam liver radiation therapy results. The half century experience has something to be borrowed: the volume effect, according to which the smaller the fraction of the irradiated liver volume, the higher the tolerated dose. Different tolerance for different underlying disease or previous non radiation treatment is to be expected. Radiobiological models experience also has to be inherited, but not their dose reference values. Then we report the published dosimetric experience about (90)Y microsphere radioembolization of primary and metastatic liver tumours. In addition we also present original data from our growing preliminary experience of more refined (99m)Tc MAA SPECT based calculations in hepatocarcinoma patients. This overcame the mean dose approach in favour of the evaluation of dose distribution at voxel level. An insight into dosimetry issues at microscopic level (lobule level) is also provided, from which the different radiobiological behaviour between resin and glass spheres can be understood. For tumour treatment, an attenuation corrected (99m)Tc- SPECT based treatment planning strategy can be proposed, although quantitative efficacy thresholds should be differentiated according to the kind of pathology and previous treatment. For non tumour liver parenchyma, data in favour of a relationship between absorbed dose and dangerous effects are encouraging. Unfortunately in hepato-cellular carcinoma, some confounding factors may hamper the adequate estimation of the risk of toxicity. First there is a lack of consensus about the exact definition of toxicity after (90)Y microsphere radioembolization. Second, for HCC patients, progression of both cancer and cirrhosis can simulate a radioinduced toxicity, making the analysis more complex.


Development of a sensitive ELISA for the determination of microcystins in algae.
Polyclonal antibodies for microcystin-leucine-arginine (MCYST-LR) were generated from rabbits after immunizing the animals with MCYST-LR conjugated with gamma-globulin. A competitive direct enzyme-linked immunosorbent assay (cdELISA) and a competitive indirect ELISA (ciELISA) were used for the characterization of the antibodies and for analysis of the toxin in algal cultures and dietary supplements. The concentrations causing 50% inhibition (IC(50)) of binding of MCYST-horseradish peroxidase (MCYST-HRP) to the solid-phase antibodies by MCYST-LR, MCYST-arginine-arginine variant (MCYST-RR), MCYST-tyrosine-arginine variant (MCYST-YR), and nodularin (NODLN) in the cdELISA were found to be 0.10, 0.12, 0.14, and 0.20 ng/mL, respectively. In the presence of algae matrix, the detection limit is less than 10 ppb. The overall analytical recovery of MCYST-LR (25 to 500 ng/g) added to the algal dietary supplements and then extracted with 0.1 M ammonium bicarbonate in the cdELISA was found to be 83.7%. Analysis of MCYSTs in algal cultures and dietary supplements showed that six of eleven cultures produce MCYSTs, and five of the algal cultures were not MCYST producers. Eight of eleven tested commercial algal dietary supplements contained MCYSTs at a level lower than 100 ppb. The presence of MCYST-LR in the Microcystis aeruginosa culture was confirmed by high-performance liquid chromatography.


Neuroprotection of ischemic preconditioning is mediated by thioredoxin 2 in the hippocampal CA1 region following a subsequent transient cerebral ischemia.
Preconditioning by brief ischemic episode induces tolerance to a subsequent lethal ischemic insult, and it has been suggested that reactive oxygen species are involved in this phenomenon. Thioredoxin 2 (Trx2), a small protein with redox-regulating function, shows cytoprotective roles against oxidative stress. Here, we had focused on the role of Trx2 in ischemic preconditioning (IPC)-mediated neuroprotection against oxidative stress followed by a subsequent lethal transient cerebral ischemia. Animals used in this study were randomly assigned to six groups; sham-operated group, ischemia-operated group, IPC plus (+) sham-operated group, IPC + ischemia-operated group, IPC + auranofin (a TrxR2 inhibitor) + sham-operated group and IPC + auranofin + ischemia-operated group. IPC was subjected to a 2 minutes of sublethal transient ischemia 1 day prior to a 5 minutes of lethal transient ischemia. A significant loss of neurons was found in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) in the ischemia-operated-group 5 days after ischemia-reperfusion; in the IPC + ischemia-operated-group, pyramidal neurons in the SP were well protected. In the IPC + ischemia-operated-group, Trx2 and TrxR2 immunoreactivities in the SP and its protein level in the CA1 were not significantly changed compared with those in the sham-operated-group after ischemia-reperfusion. In addition, superoxide dismutase 2 (SOD2) expression, superoxide anion radical ( O2-) production, denatured cytochrome c expression and TUNEL-positive cells in the IPC + ischemia-operated-group were similar to those in the sham-operated-group. Conversely, the treatment of auranofin to the IPC + ischemia-operated-group significantly increased cell damage/death and abolished the IPC-induced effect on Trx2 and TrxR2 expressions. Furthermore, the inhibition of Trx2R nearly cancelled the beneficial effects of IPC on SOD2 expression, O2- production, denatured cytochrome c expression and TUNEL-positive cells. In brief, this study shows that IPC conferred neuroprotection against ischemic injury by maintaining Trx2 and suggests that the maintenance or enhancement of Trx2 expression by IPC may be a legitimate strategy for therapeutic intervention of cerebral ischemia.


Polyamines and plant stress: activation of putrescine biosynthesis by osmotic shock.
The putrescine content of oat leaf cells and protoplasts increases up to 60-fold within 6 hours of exposure to osmotic stress (0.4 to 0.6 molar sorbitol). Barley, corn, wheat, and wild oat leaves show a similar response. Increased arginine decarboxylase activity parallels the rise in putrescine, whereas ornithine decarboxylase remains unchanged. DL-alpha-Difluoromethylarginine, a specific irreversible inhibitor of arginine decarboxylase, prevents the stress-induced rise in increase in arginine decarboxylase activity and putrescine synthesis, indicating the preferential activation of this pathway.


Extreme temperatures and paediatric emergency department admissions.
Children are particularly vulnerable to the effects of extreme temperatures. To examine the relationship between extreme temperatures and paediatric emergency department admissions (EDAs) in Brisbane, Australia, during 2003-2009. A quasi-Poisson generalised linear model combined with a distributed lag non-linear model was used to examine the relationships between extreme temperatures and age-, gender- and cause-specific paediatric EDAs, while controlling for air pollution, relative humidity, day of the week, influenza epidemics, public holiday, season and long-term trends. The model residuals were checked to identify whether there was an added effect due to heat waves or cold spells. There were 131 249 EDAs among children during the study period. Both high (RR=1.27; 95% CI 1.12 to 1.44) and low (RR=1.81; 95% CI 1.66 to 1.97) temperatures were significantly associated with an increase in paediatric EDAs in Brisbane. Male children were more vulnerable to temperature effects. Children aged 0-4 years were more vulnerable to heat effects and children aged 10-14 years were more sensitive to both hot and cold effects. High temperatures had a significant impact on several paediatric diseases, including intestinal infectious diseases, respiratory diseases, endocrine, nutritional and metabolic diseases, nervous system diseases and chronic lower respiratory diseases. Low temperatures were significantly associated with intestinal infectious diseases, respiratory diseases and endocrine, nutritional and metabolic diseases. An added effect of heat waves on childhood chronic lower respiratory diseases was seen, but no added effect of cold spells was found. As climate change continues, children are at particular risk of a variety of diseases which might be triggered by extremely high temperatures. This study suggests that preventing the effects of extreme temperature on children with respiratory diseases might reduce the number of EDAs.


Acoustic field prediction for a single planar continuous-wave source using an equivalent phased array method.
Phased array theory is combined with the Rayleigh-Sommerfeld diffraction integral to predict measured acoustic fields generated by a single-source ultrasonic transducer. The idea is to treat a single-source as a "phased array," which is composed of many small elements. The goal is to find the excitation source for the phased array, that is, the amplitude and phase for each array element, which produces an acoustic field similar to the experimentally measured field generated by the single-source transducer. A pressure field measured at a given plane parallel and close to the face of the transducer in degased water was used to calculate the excitation source of the equivalent phased array using an inverse technique. The excitation source of the equivalent phased array was then used to calculate the acoustic field from this measurement plane to the far field. It was demonstrated that this phased array approach accurately predicted the location of major grating lobes and the general distributions of the near and far pressure fields for four different transducers. This equivalent phased array method (EPAM) used to model a single-source transducer should be useful in both diagnostic and therapeutic ultrasound applications.


A conceptual framework for analysing partnership and synergy in a global health alliance: case of the UK Public Health Rapid Support Team.
Partnerships have become increasingly important in addressing complex global health challenges, a reality exemplified by the COVID-19 pandemic and previous infectious disease epidemics. Partnerships offer opportunities to create synergistic outcomes by capitalizing on complimentary skills, knowledge and resources. Despite the importance of understanding partnership functioning, research on collaboration is sparse and fragmented, with few conceptual frameworks applied to evaluate real-life partnerships in global health. In this study, we aimed to adapt and apply the Bergan Model of Collaborative Functioning (BMCF) to analyse partnership functioning in the UK Public Health Rapid Support Team (UK-PHRST), a government-academic partnership, dedicated to outbreak response and research in low- and middle-income countries. We conducted a literature review identifying important elements to adapt the framework, followed by a qualitative case study to characterize how each element, and the dynamics between them, influenced functioning in the UK-PHRST, exploring emerging themes to further refine the framework. Elements of the BMCF that our study reinforced as important included the partnership's mission, partner resources (skills, expertise and networks), leadership, the external environment, management systems and communication. Additional elements identified in the literature and critical to partnership functioning of the UK-PHRST included governance and financial structures adopted, trust and power balance, organizational culture, strategy and evaluation and knowledge management. Because of the way the UK-PHRST was structured, fostering team cohesion was an important indicator of synergy, alongside collaborative advantage. Dividing the funding and governance equally between organizations was considered crucial for maintaining institutional balance; however, diverse organizational cultures, weak communication practices and perceived power imbalances compromised team cohesion. Our analysis allowed us to make recommendations to improve partnership functioning at a critical time in the evolution of the UK-PHRST. The analysis approach and framework presented here can be used to evaluate and strengthen the management of global health partnerships to realize synergy.


Arthroscopic meniscus repair in the ACL-deficient knee.
Between 1985 and 1995, 45 patients underwent closed meniscus repair. There were 30 men and 15 women with a mean age of 32.5 years. In 23 patients, the anterior cruciate ligament was intact (group 1) whereas it was deficient in 22 patients (group 2). All patients were managed with the same postoperative program of partial weight bearing, immediate motion and rehabilitation of the knee. Five patients had a failed meniscal repair and underwent a repeat arthroscopy and a partial meniscectomy. These patients were considered as failures and excluded from the final scoring. After a mean follow-up of more than 9 years, all patients were subjected to a clinical examination using the Hospital for Special Surgery (HSS) knee rating system. Seven patients in group 2 had episodes of frequent giving way and had their anterior cruciate ligament (ACL) reconstructed 6 and 7 years after the initial meniscus repair. None of the other patients had any clinical symptoms or signs of a meniscal tear. In group 1, 20 patients and in group 2, 14 patients, all had a satisfactory knee score. Even though the failure rate of meniscus repair may be greater in an unstable knee, it is concluded that meniscal repair is not contraindicated in a knee with a deficient ACL.


Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome.
A small-cell lung carcinoma (SCLC) is found in 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumors early in newly diagnosed patients with LEMS to offer optimal patient treatment. A large nationwide cohort study of consecutive patients in the Netherlands, seen between 1990 and 2007, were screened for the presence of a tumor using chest x-ray, computed tomography of the thorax (CT-thorax), [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), bronchoscopy, and/or mediastinoscopy. SCLC was found in 54 patients, and in 46 patients, no tumor was found during a median follow-up of 8 years (range, 3 to 26 years). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening, CT-thorax detected an SCLC in 45 patients (83%), whereas chest x-ray found the tumor in only 23 patients (51%). An SCLC was found during secondary screening in another nine patients (median, 3 months; range, 1 to 41 months). In six patients, a lung tumor was found by CT-thorax or FDG-PET, and in three patients, extrapulmonary metastases were found, initially without identifiable tumor mass on CT-thorax. In almost all patients (96%), the SCLC was found within 1 year of diagnosis. CT-thorax scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.


Theoretical and experimental investigation on the intersystem crossing kinetics in benzothioxanthene imide luminophores, and their dependence on substituent effects.
In spite of their remarkable luminescence properties, benzothioxanthene imide (BTXI, an imide containing rylene chromophores) derivatives have been largely overlooked compared to their perylene bisimide and naphthalene bisimide counterparts. Thus, their detailed photophysics are much less understood. In this paper, we show how relatively simple structural modifications of the backbone of BTXIs can lead to impressive variations in their inter-system crossing kinetics. Thus, through rational engineering of their structure, it is possible to obtain a triplet formation quantum yield that reaches unity, making BTXI a promising class of compounds for triplet-based applications (photodynamic therapy, electroluminescence, etc.).


[A histochemical study of the glandular system of the human epiglottis. The clinical implications].
The paper deals about classical histologic and histochemical study for mucinoid substances through 7 laryngeal pieces coming from clinic autopsies. The gland units occurring in the two lower thirds of the epiglottis were formed by a great number of serous acini and mucinous tubuli, which secretion is acid and neutral mucous substances, as sialomucins, serving as lubricant and protective means. This glandular system convey through the epiglottic perforans holes, without break, the pre-epiglottic and epiglottic spaces, with the clinical repercussion that suggest the chance of encroachment for incipient epiglottic cancer to pre-epiglottic room.


Treatment of unscheduled bleeding in continuous oral contraceptive users with doxycycline: a randomized controlled trial.
To estimate whether doxycycline, a matrix metalloproteinase inhibitor, would decrease unscheduled bleeding associated with initiation of a continuous oral contraceptive pill. Participants initiating a continuous oral contraceptive pill (20 micrograms of ethinyl estradiol/90 micrograms of levonorgestrel) were randomly assigned to receive either doxycycline (100 mg orally twice daily) or placebo taken for 5 days at the onset of each bleeding or spotting episode during the first 84 days of the study period. For the final 28 days of the study, participants were observed on the oral contraceptive pill alone. The primary outcome was the number of bleeding and spotting days. A sample size of 66 (33 in each arm) was calculated to detect a 50% reduction in bleeding (beta=0.80, alpha=0.05) and accounted for a 30% dropout rate. Sixty-six women were randomly assinged (33 in each study group). There were no significant differences during the 84-day treatment in bleeding or spotting days (doxycycline [mean {standard error}, placebo, P=.32) or the length of the longest bleeding or spotting episode (doxycycline, placebo, P=.70) between study groups. Similarly, no significant differences in bleeding patterns existed between groups during the final 28 days. Doxycycline, administered once bleeding has started, does not decrease unscheduled bleeding or shorten episodes of unscheduled bleeding in continuous oral contraceptive pill users. I.


Engineering β-sheets employing N-methylated heterochiral amino acids.
There is a lack of functional group diversity in the reverse turn motifs nucleating a β-sheet conformation in designed peptides, proteins and foldamers. The majority of these sequences consist of d-Pro-l-Pro, d-Pro-Gly or Asn-Gly as the turn inducing motif restricting their biological application and physicochemical modulation. In this report, for the first time we elucidate that N-methylation of heterochiral amino acids in linear peptides nucleates β-sheet conformation without the necessity of having a ring or covalent constraint at the reverse turn. Our results show that d-Pro can be conveniently substituted by any other N-methylated d-amino acid followed by an N-methylated l-amino acid or sarcosine to adopt a βII' turn inducing the β-sheet folding. Furthermore, we reveal that a single amino acid either at the i + 1 or i + 2 site of the reverse turn can modulate the right-handed twist, which eventually dictates the extent of the foldedness of the β-hairpin.


Contribution of large genomic rearrangements in Italian Lynch syndrome patients: characterization of a novel alu-mediated deletion.
Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.


Nanoparticle decoration impacts airborne fungal pathobiology.
Airborne fungal pathogens, predominantly Aspergillus fumigatus, can cause severe respiratory tract diseases. Here we show that in environments, fungal spores can already be decorated with nanoparticles. Using representative controlled nanoparticle models, we demonstrate that various nanoparticles, but not microparticles, rapidly and stably associate with spores, without specific functionalization. Nanoparticle-spore complex formation was enhanced by small nanoparticle size rather than by material, charge, or "stealth" modifications and was concentration-dependently reduced by the formation of environmental or physiological biomolecule coronas. Assembly of nanoparticle-spore surface hybrid structures affected their pathobiology, including reduced sensitivity against defensins, uptake into phagocytes, lung cell toxicity, and TLR/cytokine-mediated inflammatory responses. Following infection of mice, nanoparticle-spore complexes were detectable in the lung and less efficiently eliminated by the pulmonary immune defense, thereby enhancing A. fumigatus infections in immunocompromised animals. Collectively, self-assembly of nanoparticle-fungal complexes affects their (patho)biological identity, which may impact human health and ecology.


Treatment with EGF increases the length of S-Phase after partial hepatectomy in rat, changing the activities of cdks.
Liver proliferation occurs in the presence of mitogenic stimuli such as partial hepatectomy or growth factors. In this work we investigate how partial hepatectomy and Epidermal Growth Factor (EGF) affect hepatocyte proliferation by modulating cell cycle regulators. EGF administered to non-operated rats increased PCNA (proliferating cell nuclear antigen) expression, whereas when EGF was administered to partially hepatectomized rats it was able to anticipate the increase in PCNA expression to 18h after PH and to prolong it to 34h. Cell cycle progression was examined by monitoring specific markers of late G1- and S-phases. Western blot analysis showed that both treatment with EGF alone and treatment with EGF after PH induce the expression of cyclins D1 and A and of p21(cip1), but inhibites the expression of cyclin E and p27(kip1). EGF administration after PH also significantly affected the activity of the cyclin D1-cdk4 and cyclin E-cdk2 complexes, mainly by changing their time progression: it accelerated the increase in activity to 18h and caused a subsequent drop in activity after 34h; it delayed the activity of the cyclin A-cdk2 complex to 34h. In conclusion we observed that EGF modulates the activity of cdk complexes and induces a different linkage with inhibitory proteins that demonstrates their dual role, depending on their association with different cyclin-cdk complexes.


Comparison of clinical utility between diaphragm excursion and thickening change using ultrasonography to predict extubation success.
Both diaphragmatic excursion and change in muscle thickening are measured using ultrasonography (US) to assess diaphragm function and mechanical ventilation weaning outcomes. However, which parameter can better predict successful extubation remains to be determined. The aim of this study was to compare the clinical utility of these two diaphragmatic parameters to predict extubation success. This study included patients subjected to extubation trial in the medical or surgical intensive care unit of a university-affiliated hospital from May 2015 through February 2016. Diaphragm excursion and percent of thickening change (Δtdi%) were measured using US within 24 hours before extubation. Sixty patients were included, and 78.3% (47/60) of these patients were successfully extubated, whereas 21.7% (13/60) were not. The median degree of excursion was greater in patients with extubation success than in those with extubation failure (1.65 cm vs. 0.8 cm, p < 0.001). Patients with extubation success had a greater Δtdi% than those with extubation failure (42.1% vs. 22.5%, p = 0.03). The areas under the receiver operating curve for excursion and Δtdi% were 0.836 (95% confidence interval [CI], 0.717 to 0.919) and 0.698 (95% CI, 0.566 to 0.810), respectively (p = 0.017). Diaphragm excursion seems more accurate than a change in the diaphragm thickness to predict extubation success.


[The modern approaches to the treatment of chronic suppurative otitis with cholesteatoma].
The objective of the present study was to evaluate the long-term outcomes of the surgical treatment of chronic suppurative otitis with cholesteatoma in terms of prevention of a residual disease and its relapses. The results of the postoperative observation of 149 patients during the period from 2009 till 2013 are presented. All the patients underwent sanation surgery with the obliteration of paratympanic spaces followed by the restoration of the posterior wall of the external auditory meatus and simultaneous tympanoplasty (closed-type surgery). The patients were examined one year after the treatment with the use of the MRI technology in the non-EPI DWI regime for the purpose of monitoring the residual disorders and relapses of cholesteatoma. The follow-up observation revealed 9 cases of residual cholesteatoma, no relapse of chronic suppurative otitis was documented.


Evaluation of radical scavenging activity of fresh and air-dried tomatoes by three model reactions.
The radical scavenging activity and the antioxidant content of fresh and air-dried tomatoes were investigated. Tomato halves were dried in a pilot-scale dryer under the following conditions: air temperature, 80 degrees C; air flow rate, 1.5 m/s; drying time, 400 min; final moisture, 25%. Carotenoid (lycopene, beta-carotene, lutein) and ascorbic acid were analyzed by HPLC with a spectrophotometric and an electrochemical detector, respectively. Total phenolics were determined by using the Folin-Ciocalteu reagent. The radical scavenging activity was studied in three model systems: (a) the xanthine oxidase and xanthine system, which generates superoxide radical and hydrogen peroxide; (b) the 3-morpholinosydnonimine system, which releases spontaneously superoxide radical and nitrogen monoxide, forming peroxynitrite; (c) the linoleic acid and CuSO(4) system, which promotes lipid peroxidation. These model systems allow the simulation of key reactions involved in the pathogenesis of certain chronic diseases and may be related to the in vivo activity of tomato antioxidants. Hence, these measurements can be used for optimizing tomato processing and storage. The drying process resulted in a decrease of ascorbic acid content, whereas phenol reagent reducing compounds increased. Carotenoid levels were substantially unchanged upon drying. Fresh and air-dried tomato extracts could act as radical scavengers both in the reactive oxygen species-mediated reactions and in lipid peroxidation. Drying affected the antioxidant effectiveness as measured in the xanthine/xanthine oxidase system, which was found to be the most sensitive method for the measurement of tomato antioxidant activity (lower I(50)) but retained the antioxidant effectiveness in the other two systems.


Testing standard methods of dental age estimation by Moorrees, Fanning and Hunt and Demirjian, Goldstein and Tanner on three South African children samples.
Dental age estimation of juvenile skeletal remains has utilized the methods of Moorrees ,Fanning and Hunt (1963) [MFH] and Demirjian,Goldstein and Tanner (1973) [DGT] for many years with various results. The Demirjian et al method has been tested by several authors on their population groups with varying results.The use of these methods to age the skeletal remains of South African children by the author has not been successful. The aim of this study was to test the accuracy of the dental age estimation methods of MFH and DGT on samples of children of different ethnic groups.The study showed that the MFH method consistently under-estimates the age and the method of Demirjian et al over-estimates theages.


In Vivo Virulence Characterization of Pregnancy-Associated Listeria monocytogenes Infections.
Listeria monocytogenes is a foodborne pathogen that infects the placenta and can cause pregnancy complications. Listeriosis usually occurs as a sporadic infection, but large outbreaks are also reported. Virulence from clinical isolates is rarely analyzed due to the large number of animals required, but this knowledge could help guide the response to an outbreak. We implemented a DNA barcode system using signature tags that allowed us to efficiently assay variations in virulence across a large number of isolates. We tested 77 signature-tagged clones of clinical L. monocytogenes strains from 72 infected human placentas and 5 immunocompromised patients, all of which were isolated since 2000. These strains were tested for virulence in a modified competition assay in comparison to that of the laboratory strain 10403S. We used two in vivo models of listeriosis: the nonpregnant mouse and the pregnant guinea pig. Strains that were frequently found at a high abundance within infected organs were considered hypervirulent, while strains frequently found at a low abundance were considered hypovirulent. Virulence split relatively evenly among hypovirulent strains, hypervirulent strains, and strains as virulent as 10403S. The laboratory strain was found to have an intermediate virulence phenotype, supporting its suitability for use in pathogenesis studies. Further, we found that splenic virulence and placental virulence are closely linked in both the guinea pig and mouse models. This suggests that outbreak and sporadic pregnancy-associated L. monocytogenes strains are not generally more virulent than lab reference strains. However, some strains did show consistent and reproducible virulence differences, suggesting that their further study may reveal deeper insights into the biological underpinnings of listeriosis.


Utility of the von Willebrand factor collagen binding assay in the diagnosis of von Willebrand disease.
von Willebrand Disease (VWD) is the most common inherited bleeding disorder and also arises as an acquired defect (AVWS). VWD and AVWS are due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), an adhesive plasma protein with multiple activities. Diagnosis of VWD is problematic, being subject to overdiagnosis, underdiagnosis, and misdiagnosis. This is largely due to limitations in current test procedures and an over-reliance on these imperfect test systems for clinical diagnosis. VWF essentially acts to assist in the formation of a platelet thrombus to stop blood loss from sites of injury, achieving this by binding to platelets (primarily through the glycoprotein Ib receptor), binding to subendothelial matrix components (primarily collagen), and binding to factor VIII (FVIII), thus protecting FVIII from degradation and enabling its delivery to sites of vascular injury. VWD is classified into six separate types, which may each be differentially managed therapeutically, and this underscores the importance of a correct diagnosis. The current report concisely reviews the utility of a relatively underutilised assay, the VWF collagen binding assay (VWF:CB), in facilitating the correct diagnosis and typing of VWD. In particular, if laboratories do not utilise the VWF:CB, then (i) type 2M VWD will continue to be missed, and/or misdiagnosed as types 2A or 1 VWD, and (ii) types 2A, 2B and PT-VWD will continue to be missed, or else be misdiagnosed as type 1 VWD or ITP. Am. J. Hematol. 92:114-118, 2017. © 2016 Wiley Periodicals, Inc.


Ageing and alpha-adrenoceptors.
Ageing changes in alpha-adrenoceptors can be summarized as follows: except in the eye, where there is an apparent increased responsiveness with increasing age in man, peripheral alpha-adrenoceptor responsiveness has generally been found to be either unchanged or reduced with increasing age in animals and man. Even where changes have been found it remains to be clarified whether these changes are selective changes in alpha-receptors or whether they are due to alterations in responsiveness beyond the level of the receptor.


Six myths that can cloud strategic vision.
Strategic planners must guard against relying on false assumptions that interfere with organizational growth. Six myths that can sidetrack innovative strategy are: Higher occupancy means improved financial performance; the growing elderly population will fill empty hospital beds; physical assets define hospital capacity; "enhance payer mix" is a truly strategic objective; information is power; and capital is a limiting resource.


Quality assessment of health counseling: performance of health advisors in cardiovascular prevention.
Quality assessments of interventions are seen as essential in optimizing their implementation, interpreting their effectiveness, and illuminating their underlying processes. In Hartslag Limburg, a cardiovascular prevention project, the quality of a health counseling intervention was assessed as part of the process evaluation. Four health advisors each video-taped 16 counseling sessions, all of which were assessed by three independent observers. Health counseling was found to be a very difficult skill, but, all things considered, the overall quality was evaluated as rather encouraging. No indication was found of quality improvement over time. The interpretation of the findings was complicated by limited absolute interobserver agreement, but reliable relative distinctions could be made between the health advisors' performance and their application of various counseling skills. Future quality investigators are advised to carefully match study goals with study methods, and practitioners planning a health counseling project should take the complexity of the task into account.


Synthesis, anticonvulsant and antimicrobial activities of some new [1-(2-naphthyl)-2-(pyrazol-1-yl)ethanone]oxime ethers.
In this study, 12 new oxime ether derivatives, which were expected to show anticonvulsant and antimicrobial activities, were synthesized. Oxime ether derivatives were synthesized by the reaction of various alkyl halides with 1-(2- naphthyl)-2-(pyrazol-1-yl)ethanone oxime. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazol (ScM) seizure tests, while neurological disorders were evaluated using rotorod toxicity test according to the ASP of NIH. Compound 1, 6 and 7 showed anticonvulsant activity at 300 mg/kg dose at 4 h, but compounds 1 and 7 showed toxicity at 300 mg/kg dose at half an hour. Antimicrobial activities of the compounds were also determined using agar microdilution method. Compound 1 and 5 were found to have the highest antifungal activity among the other compounds.


Genetic diversity and phylogeny of rhizobia isolated from Caragana microphylla growing in desert soil in Ningxia, China.
Rhizobia are soil bacteria with the capacity to induce nitrogen-fixing nodules on the roots or stems of legume plants. A total of 40 bacterial isolates from the root nodules of Caragana microphylla growing in desert soil in Ningxia, China, were analyzed for genetic diversity and phylogenetic position. These isolates were classified into 7 types of 16S ribosomal DNA (rDNA) using polymerase chain reaction-restriction fragment length polymorphism analysis. They were grouped into 4 clades, Rhizobium-Agrobacterium, Sinorhizobium, Phyllobacterium, and Bradyrhizobium, when the phylogenies of 16S rDNA, recA, and atpD genes were applied. Phylogenetic analysis showed that the tree generated from the 16S rDNA sequencing agreed with that produced from the recA and atpD genes. By analyzing phylogenetic relationship using the 3 loci, the isolates in the branches of Phyllobacterium and Sinorhizobium could be identified as P. brassicacearum and S. meliloti. The isolates in the branch of Rhizobium-Agrobacterium were the most abundant microsymbiont of C. microphylla and were designated R. leguminosarum, R. galegae, R. alamii, and A. tumefaciens. Two isolates with low sequence similarity to the known species of Bradyrhizobium might be novel species in this genus.


Role of the plasma brain natriuretic peptide in differentiating patients with congestive heart failure from other diseases.
Heart failure (HF) is primarily a disease of the elderly. The incidence of congestive heart failure (CHF) in Thailand has been increasing during the last 10 years. Unlike other diseases, physicians have only rough patients' symptoms and physical findings to guide the adequacy of treatment. Recently, there has been evidence of the role of brain natriuretic peptide (BNP) and its use in HF concerning diagnosis, prognosis, and treatment follow-up. The purpose of this study was to determine the sensitivity and specificity of N-terminal part of brain natriuretic peptide plasma level (NT-proBNP) in the diagnosis of HF in Thai patients who presented with dyspnea. The design was a cross sectional study. The authors enrolled 50 consecutive patients from the Respiratory Unit with dyspnea from chronic obstructive pulmonary disease (COPD), asthma, or anxiety. The cardiovascular cause of dyspnea such as pulmonary emboli and poor left ventricular ejection fraction (LVEF) were excluded. Forty eight consecutive patients with evidence of HF who presented to the Cardiac Center with a history of dyspnea on exertion were assigned as cases. Five milliliters of venous blood samples were taken and sent together with 200 samples from a normal healthy population from the check up department for NT-proBNP measurement. In case and control groups, there were no statistical significances in sex (males 68.8% vs females 52.0%, p > 0.05) and age (63.3 +/- 14.9 vs 55.6 +/- 16.9; p > 0.05). The mean left ventricular ejection fraction in the case group was 32.4 +/- 9.7 per cent. There was significant difference between value of NT-proBNP in the control group (386 +/- 1,041 pg/ml) and in the case group (8,912 +/- 12,525 pg/ml, p < 0.001). To diagnose HF in patients who presented with dyspnea using the cut-off value of NT-proBNP at > 150 pg/ml in patients with dyspnea the sensitivity was 96 per cent, and the specificity of 72 per cent; at > 200 pg/ml the sensitivity was 96 per cent and the specificity was 80 per cent and at > 300 pg/ml the sensitivity was 94 per cent and specificity of 82 per cent. Plasma level of NT-proBNP increased significantly with increasing New York Heart Association (NYHA) functional class (class II: 1,107 +/- 1,091 pg/ml; class III: 5,097 +/- 4,201 pg/ml, class IV: 19,389 +/- 15,966 pg/ml p < 0.01). There was no significant difference of plasma NT-proBNP levels in patients with ischemic (8,586 +/- 11,601 pg/ml; n = 35) and those with non ischemic cardiomyopathy (9,789 +/- 15,229 pg/ml; n = 13). Plasma NT-proBNP was associated with neck vein distension (p < 0.05) but there was no significant association with S3, paroxysmal nocturnal dyspnea, rales, cardiomegaly, acute pulmonary edema, serum sodium (r = 0.22), ejection fraction (r = -0.18) and subsequent hospital death (p > 0.05). Measurement of plasma NT-proBNP proved to be a useful diagnostic test in differentiating HF from other causes in patients who presented with dyspnea.


HIV treatment cascade among female sex workers in Ethiopia: Assessment against the UNAIDS 90-90-90 targets.
HIV treatment cascades for HIV-positive female sex workers (FSWs) have been challenged by the overlapping stigma and discrimination associated with both their sex work and HIV status. This study aims to assess the proportion of HIV-positive FSWs who access care and treatment in Ethiopia. A cross-sectional study with a respondent-driven sampling technique was used to enroll 6,085 female sex workers from January to June 2020. Interviews were conducted to assess the FSWs' HIV status awareness and access to ART. A blood sample was drawn to determine the current HIV status and viral load level. Logistic regression was run to identify factors associated with FSWs' HIV status awareness. Of the total 1140 HIV-positive FSWs, 50.38% knew they were HIV positive; 92.88% of those who knew their status were on ART, and 91.68% of those on ART had attained viral suppression of less than 1000 copies per milliliter. The adjusted odds of knowing HIV status was 3.20 (95% CI; 2.00, 5.13) among those aged 35 years and older, 1.81 (95% CI; 1.05, 3.12) among widowed, and 1.73 (95% CI; 1.28, 2.32) in those who did not perceive the risk of HIV acquisition. Only about half of HIV-positive FSWs knew they were HIV positive. More than 90% of those who knew their status were put on ART and achieved viral suppression. The weakest point in achieving HIV control among FSWs is the identification of those living with HIV.


Linking process and outcome in the community reinforcement approach for treating cocaine dependence: a preliminary report.
This preliminary study evaluated the relationship between therapy process variables (mechanistic processes and interpersonal processes), and treatment outcome (i.e., retention and cocaine abstinence) among 16 cocaine-dependent pregnant or postpartum women treated with the Community Reinforcement Approach (CRA). Two new rating scales were developed for this purpose. The Mechanisms of Action Rating Scale (MARS) assesses five CRA mechanistic domains (Big Picture goals, functional analyses of behavior, nondrug-related activities, skills training, and homework). The Interpersonal Variables Rating Scale (IVRS) measures three nonspecific or interpersonal dimensions of psychotherapy (i.e., empathy, response to resistance, and therapeutic alliance). These rating scales were used to rate one, early treatment, videotaped CRA session for each subject. Results indicated that: 1) sessions with patients who achieved three or more consecutive weeks of cocaine abstinence were rated significantly higher on therapist empathy and positive responses to resistance, and total IVRS scores (all of which indicate positive interpersonal processes); and 2) Big Picture goals, positive therapeutic alliance, and total IVRS scores were significantly and positively correlated with number of consecutive weeks of cocaine-negative urine toxicology tests. Only MARS homework scores were significantly and positively associated with number of study weeks completed. Finally, the pattern of interrelationships among the MARS subdomains suggests the coherence of the multifaceted CRA treatment. The findings of this preliminary study suggest the importance of monitoring both mechanistic and interpersonal processes during CRA treatment of cocaine dependence.


Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer.
Early detection is a crucial element for the timely diagnosis and successful treatment of all human cancers but is limited by the sensitivity of current imaging methodologies. We have synthesized and studied bioresorbable calcium phosphate nanoparticles (CPNPs) in which molecules of the near-infrared (NIR) emitting fluorophore, indocyanine green (ICG), are embedded. The ICG-CPNPs demonstrate exceptional colloidal and optical characteristics. Suspensions consisting of 16 nm average diameter particles are colloidally stable in physiological solutions (phosphate buffered 0.15 M saline (PBS), pH 7.4) with carboxylate or polyethylene glycol (PEG) surface functionality. ICG-doped CPNPs exhibit significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore, consistent with the multiple molecules encapsulated per particle. The quantum efficiency per molecule of the ICG-CPNPs is 200% greater at 0.049 +/- 0.003 over the free fluorophore in PBS. Photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. PEGylated ICG-CPNPs accumulate in solid, 5 mm diameter xenograft breast adenocarcinoma tumors via enhanced retention and permeability (EPR) within 24 h after systemic tail vein injection in a nude mouse model. Ex situ tissue imaging further verifies the facility of the ICG-CPNPs for deep-tissue imaging with NIR signals detectable from depths up to 3 cm in porcine muscle tissue. Our ex vivo and in vivo experiments verify the promise of the NIR CPNPs for diagnostic imaging in the early detection of solid tumors.


Bone marrow cell cotransplantation with islets improves their vascularization and function.
BACKGROUND.: To test the angiogenesis-promoting effects of bone marrow cells when cotransplanted with islets. METHODS.: Streptozotocin-induced diabetic BALB/c mice were transplanted syngeneically under the kidney capsule: (1) 200 islets, (2) 1 to 5x10 bone marrow cells, or (3) 200 islets and 1 to 5x10 bone marrow cells. All mice were evaluated for blood glucose, serum insulin, and glucose tolerance up to postoperative day (POD) 28, and a subset was monitored for 3 months after transplantation. Histologic assessment was performed at PODs 3, 7, 14, 28, and 84 for the detection of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), insulin, cluster of differentiation-34, and pancreatic duodenal homeobox-1 (PDX-1) protein. RESULTS.: Blood glucose was the lowest and serum insulin was the highest in the islet+bone marrow group at POD 7. Blood glucose was significantly lower in the islet+bone marrow group relative to the islet only group after 63 days of transplantation (P<0.05). Significantly more new periislet vessels were detected in the islet+bone marrow group compared with the islet group (P<0.05). Vascular endothelial growth factor staining was more prominent in bone marrow than in islets (P<0.05). Pancreatic duodenal homeobox-1-positive areas were identified in bone marrow cells with an increase in staining over time. However, there were no normoglycemic mice and no insulin-positive cells in the bone marrow alone group. CONCLUSIONS.: Cotransplantation of bone marrow cells with islets is associated with enhanced islet graft vascularization and function.


Dynamic Fascial Closure With Vacuum-Assisted Wound Closure and Mesh-Mediated Fascial Traction (VAWCM) Treatment of the Open Abdomen-An Updated Systematic Review.
Introduction: Several different temporary abdominal closure techniques are described in the context of open abdomen treatment. Techniques based on dynamic fascial closure combined with negative pressure therapy have gained popularity and seem to result in the highest fascial closure rates without increased complications and are highlighted in recent guidelines and recommendations. One dynamic closure technique is the vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) technique, first described in 2007. The aim of this systematic review was to evaluate the VAWCM technique regarding a number of short- and long-term results. Materials and Methods: A systematic literature search was performed in PubMed, EMBASE, and Cochrane Library databases for articles published between January 1, 2006 and May 8, 2020. The review was independently performed by the two authors according to the PRISMA statements for reporting systematic reviews and meta-analyses. Results were pooled for presentation of weighted means when applicable. Results: A total of 220 articles were screened by title and abstract. Thirty-two articles were assessed for eligibility by full-text review and 15 articles finally remained for review. A total of 600 patients treated with VAWCM were included. The pooled weighted means were as follows: fascial closure, 83.5%; enteroatmospheric fistula, 5.6%; planned ventral hernia, 6.2%; in-hospital survival, 72%; and incisional hernia incidence, 40.5%. Long-term survival ranged between 22 and 72%. Quality of life (SF-36) was reported in two studies showing lower scores than the population mean especially in physical domains. Incisional hernia resulted in lower scores in one but not in the other study. Discussion: The results of 600 VAWCM-treated patients from 15 studies were evaluated in this systematic review. Earlier findings with high fascial closure rates, low enteroatmospheric fistula, and planned ventral hernia rates as well as high incisional hernia incidences were underlined. Permanent mesh for efficient fascial traction and reinforcement at fascial closure seem to be the next step in evolving an optimal temporary closure technique in open abdomen treatment.


Association between Vitamin D and Short-Term Functional Outcomes in Acute Ischemic Stroke.
Vitamin D (Vit D) affects musculoskeletal performance and central nervous system neuroprotection. We aimed to investigate the association between serum Vit D levels and short-term functional outcomes in patients with acute ischemic stroke. This study involved patients with acute ischemic stroke confirmed on brain MRI. The National Institutes of Health Stroke Scale (NIHSS) was used to assess initial stroke severity upon admission. We evaluated the functional outcomes using the Berg Balance Scale (BBS), Manual Function Test (MFT), Korean Mini-Mental State Examination (K-MMSE), Korean version of the modified Barthel Index (K-MBI) within three weeks from the onset of stroke, and modified Rankin Scale (mRS) score at discharge. Overall, 192 patients were finally included and divided into three groups: Vit D sufficient (n = 28), insufficient (n = 49), and deficient (n = 115). Multivariate analysis showed that the Vit D deficient group presented with a higher risk of initially severe stroke (p = 0.025) and poor functional outcomes on the BBS (p = 0.048), MFT (p = 0.017), K-MMSE (p = 0.001), K-MBI (p = 0.003), and mRS (p = 0.032) compared to the Vit D sufficient group. Vit D deficiency may be associated with severe initial stroke and poor short-term post-stroke functional outcomes.


A Renewed Charter: Key Principles to Improve Patient Care in Severe Asthma.
Asthma is a heterogenous respiratory disease, usually associated with chronic airway inflammation and hyper-responsiveness, which affects an estimated 339 million people worldwide. Severe asthma affects approximately 5-10% of patients with asthma, approximately 17-34 million people globally, more than half of whom have uncontrolled disease. Severe asthma carries a substantial burden of disease, including unpredictable symptoms and potentially life-threatening flare-ups. Furthermore, severe asthma has a substantial burden on health care systems and economies worldwide. In 2018, a group of experts from the clinical community, patient support groups, and professional organisations joined together to develop the Severe Asthma Patient Charter, which set out six principles to define what patients should expect for the management of their severe asthma and what should constitute a basic standard of care. Since the publication of that original Charter in 2018, several important changes have occurred, including an improved understanding of asthma and effective asthma management; several new therapies have become available; and finally, the COVID-19 pandemic has placed a spotlight on respiratory conditions, the workforces that treat them, and the fundamental importance of health care system resilience. With those developments in mind, we, representatives of the academic, clinical, and patient advocacy group communities, have updated the Charter to Improve Patient Care in Severe Asthma with a focus on six principles: (1) I deserve a timely, comprehensive assessment of my asthma and its severity; (2) I deserve a timely, straightforward referral to an appropriate specialist for my asthma when it is not well controlled; (3) I deserve to understand what makes my asthma worse; (4) I deserve access to treatment and care that reduces the impact of asthma on my daily life; (5) I deserve not to be reliant on systemic corticosteroids; (6) I deserve to be involved in decisions about my treatment and care.


Identification of E6AP-independent degradation targets of HPV E6.
The high-risk Human Papillomavirus (HPV) E6 oncoprotein is known to contribute to human malignancy by targeting several of its cellular substrates through the ubiquitin-mediated degradation pathway. Previous studies have revealed that E6 interacts with the E6AP ubiquitin-protein ligase and directs its ubiquitylation activity toward several specific cellular proteins, one of the most important of which is p53. However, the role of E6AP in the degradation of many other E6 substrates is still ambiguous because loss of E6AP also induces a loss of E6 expression. To examine this further, we used CRISPR-edited E6AP knockout cells to perform E6 degradation assays in the presence of a catalytically inactive mutant form of E6AP, thus ensuring the stabilization of E6 but with the ligase itself being functionally inactive. Using this system, we found that E6 can mediate the degradation of several PDZ domain-containing proteins independently of E6AP ubiquitin ligase activity. This study thus opens up ways to investigate other possible components of the cellular ubiquitin proteasome pathway that E6 might utilize to target these substrates.