PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia.
Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis. Mice with constitutive deacetylation-mimetic PPARγ mutations on lysine residues K268 and K293 (2KR) in an LDL (low-density lipoprotein)-receptor knockout (Ldlr-/-) background (2KR:Ldlr-/-) were aged for 18 months on a standard laboratory diet to examine the cardiometabolic phenotype, which was confirmed in Western-type diet-fed 2KR:Ldlr+/- mice. Whole-liver RNA-sequencing and in vitro studies in bone marrow-derived macrophages were conducted to decipher the mechanism. In contrast to severe atherosclerosis in WT:Ldlr-/- mice, aged 2KR:Ldlr-/- mice developed little to no plaque, which was underlain by a significantly improved plasma lipid profile, with particular reductions in circulating LDL. The protection from hypercholesterolemia was recapitulated in Western-type diet-fed 2KR:Ldlr+/- mice. Liver RNA-sequencing analysis revealed suppression of liver inflammation rather than changes in cholesterol metabolism. This anti-inflammatory effect of 2KR was attributed to polarized M2 activation of macrophages. Additionally, the upregulation of core circadian component Bmal1 (brain and muscle ARNT-like 1), perceived to be involved in anti-inflammatory immunity, was observed in the liver and bone marrow-derived macrophages. PPARγ deacetylation in mice prevents the development of aging-associated atherosclerosis and hypercholesterolemia, in association with the anti-inflammatory phenotype of 2KR macrophages.


Supramolecular Singlet Fission of Pentacene Dimers within Polyaromatic Capsules.
We herein report a new set of supramolecular nanotools for the generation and modulation of singlet fission (SF) of noncovalent/covalent pentacene dimers. Two molecules of a pentacene monomer with bulky substituents are facilely encapsulated by a polyaromatic capsule, composed of naphthalene-based bent amphiphiles, in water. The encapsulated noncovalent dimer converts to otherwise undetectable triplet pairs and an individual triplet in high quantum yields (179% and 53%, respectively) even under high dilution conditions. Within the capsule, a covalently linked pentacene dimer with bulky groups generates two triplet pair intermediates in parallel, which are hardly distinguished in bulk solution, in excellent total quantum yield (196%). The yield of the individual triplet is enhanced by 1.6 times upon encapsulation. For both types of pentacene dimers, the SF features can be readily tuned by changing the polyaromatic panels of the capsule (i.e., anthracene and phenanthrene).


Association of Initial Trough Concentrations of Vancomycin with Outcomes in Pediatric Patients with Gram-Positive Bacterial Infection.
Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive infections. For adult patients, treatment with vancomycin requires effective therapeutic drug-monitoring (TDM) to achieve clinical outcomes and reduce the incidence of adverse effects. However, it remains still unclear whether the TDM with vancomycin is beneficial in yielding better clinical outcomes in pediatrics. The objective of our study was to evaluate whether the clinical response to treatment was associated with initial trough concentrations of vancomycin in pediatric patients. A retrospective observation study of 60 patients (age: 1 month-15 years) who had completed and qualified for analysis was conducted at Kyoto University Hospital. The response to treatment was assessed by the time to resolution of fever and time to 50% decline in C-reactive protein (CRP). In addition, we explored whether vancomycin trough level was associated with the baseline characteristics. Trend analysis showed that there were significant correlations between vancomycin trough level and age, body weight, estimated glomerular filtration rate, and serum albumin levels. The time to resolution of fever of the patients with higher initial trough level (≥ 5 µg/mL) was significantly lower than that of the patients with lower trough level (< 5 µg/mL). The higher vancomycin concentration tended to be associated with the shorter time to 50% decline in CRP. The findings suggest that initial trough concentration is important in achieving better outcomes with vancomycin treatment in pediatrics.


[The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing - Annual report 2018].
The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2018 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers. The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards. PM Registry: data about 23 912 PM implantations were collected (20 084 first implants and 3828 replacements). The number of collaborating centers was 180. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 34.5% of first PM implants, sick sinus syndrome in 18.3%, atrial fibrillation plus bradycardia in 13.0%, other in 34.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (19.2% of first implants). Use of single-chamber PMs was reported in 24.9% of first implants, of dual-chamber PMs in 67.6%, of PMs with cardiac resynchronization therapy (CRT) in 1.6%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 5.9%. ICD Registry: data about 18 353 ICD implantations were collected (13 944 first implants and 4359 replacements). The number of collaborating centers was 433. Median age of treated patients was 71 years (63 quartile I; 78 quartile III). Primary prevention indication was reported in 84.3% of first implants, secondary prevention in 15.7% (cardiac arrest in 5.3%). A single-chamber ICD was used in 27.9% of first implants, dual-chamber ICD in 31.9% and biventricular ICD in 40.2%. The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (http://www.aiac.it/riprid) should be adopted at large scale.


Gene structure and chromosomal localization of the murine lamin B2 gene.
The structure of the murine lamin B2 gene has been analyzed by cloning, sequencing and hybridization techniques, including in situ hybridization. The gene exists in single copy on the distal arm of chromosome 10 and comprises at least 15 kb, containing 12 exons and 11 introns. The transcriptional start point, as determined by primer extension analysis and RNase protection, was mapped to the region -264 to -254 upstream the ATG start codon. The 5' upstream region does not reveal any classical TATA box elements but typical features of genes encoding "housekeeping" proteins. The intron pattern is strikingly similar to those of the Xenopus laevis lamin LIII (Döring, V., R. Stick, EMBO J. 9, 4073-4081 (1990)) and of the intermediate filament protein of the invertebrate Helix aspersa (Dodemont, H., D. Riemer, K. Weber, EMBO J. 9, 4083-4094 (1990], particularly in the central rod and in the tail domains. Moreover, this lamin gene contains an additional intron in the region encoding the rod domain. Our data are compatible with the evolutionary hypothesis that IF proteins have evolved from a lamin-like ancestor molecule.


Respiratory aflatoxicosis: suppression of pulmonary and systemic host defenses in rats and mice.
Dietary aflatoxin B1 (AFB1) exposure impairs innate and acquired host defenses resulting in increased susceptibility to infections in domesticated animals. Experimental studies have confirmed this observation by demonstrating the immunosuppressive effects of AFB1 ingestion. In addition to being present in dietary components, AFB1 is also found in significant amounts in respirable particles of grain dust. To determine the effect of respiratory tract exposure to AFB1 on host defenses, rats and mice were exposed either by aerosol inhalation or intratracheal instillation to AFB1. Nose-only inhalation exposure of rats to AFB1 aerosols suppressed alveolar macrophage (AM) phagocytosis at an estimated dose of 16.8 micrograms/kg with the effect persisting for approximately 2 weeks. To determine whether another mode of respiratory tract exposure, intratracheal instillation, reflected inhalation exposure, animals were treated with increasing concentrations of AFB1 which also suppressed AM phagocytosis in a dose-related manner albeit at doses at least an order of magnitude more than that obtained by aerosol inhalation. Intratracheal administration of AFB1 also suppressed the release of tumor necrosis factor-alpha from AMs and impaired systemic innate and acquired immune defenses as shown, respectively, by suppression of peritoneal macrophage phagocytosis and the primary splenic antibody response. These findings demonstrate that experimental respiratory tract exposure to AFB1 suppresses pulmonary and systemic host defenses and indicates that inhalation exposure to AFB1 is an occupational hazard where exposure to AFB1-laden dust is common.


Interspecific Variation in Susceptibility to Insecticides by Lepidopteran Pests of Soybean, Cotton, and Maize Crops From Brazil.
The interspecific variation in susceptibility to insecticides by lepidopteran species of soybean [Glycine max L. (Merr.)], cotton (Gossypium hirsutum L.), and maize (Zea mays L.) crops from Brazil were evaluated. Populations of Anticarsia gemmatalis (Hübner) (Lepidoptera: Erebidae), Chrysodeixis includens (Walker), Helicoverpa armigera (Hübner), Spodoptera frugiperda (Smith), Spodoptera eridania (Stoll), Spodoptera cosmioides (Walker), and Spodoptera albula (Walker) (Lepidoptera: Noctuidae) were collected from 2019 to 2021. Early L3 larvae (F2 generation) were exposed to the formulated insecticides methoxyfenozide, indoxacarb, spinetoram, flubendiamide, and chlorfenapyr in diet-overlay bioassays. The median lethal concentrations (LC50) were used to calculate tolerance ratios (TR) of each species in relation to the most susceptible species to each insecticide. The lowest LC50 values were verified for A. gemmatalis to all insecticides tested. Chrysodeixis includens and most of the Spodoptera species were moderately tolerant to methoxyfenozide (TR < 8.0-fold) and indoxacarb (TR < 39.4-fold), whereas H. armigera was the most tolerant species to methoxyfenozide (TR = 21.5-fold), and indoxacarb (TR = 106.4-fold). Spodoptera cosmioides, S. eridania, and S. albula showed highest tolerance to spinetoram (TR > 1270-fold), S. eridania, S. frugiperda, and S. albula to flubendiamide (TR from 38- to 547-fold), and S. albula to indoxacarb (TR = 138.6-fold). A small variation in susceptibility to chlorfenapyr (TR < 4.4-fold) was found among the lepidopteran evaluated. Our findings indicate a large variation in susceptibility to indoxacarb, spinetoram, and flubendiamide and a relatively low variation in susceptibility to methoxyfenozide and chlorfenapyr by lepidopteran species of soybean, cotton, and maize from Brazil.


Field assessment of flood event suspended sediment transport from ephemeral streams in the tropical semi-arid catchments.
An assessment of suspended sediment transport was carried out in a number of semiarid catchments during flood events in order to quantify the degradation rates. In order to quantify these, a systematic sampling procedure of the episodic flood events was proposed for representative catchments. The procedure allows for an integration over the whole run-off episode using both the rising and falling limbs of the run-off hydrograph to compute the sediment quantities for each individual flood event.Higher sediment concentrations occurred in the rising limb than those at the recession for any stage of flow. The maximum suspended sediment concentration was observed at the peak of the flood hydrograph. An integration of the sediment concentration over its duration gave the total sediment yield from the flood event. For the ephemeral channels, only a small number of flood events were observed over a three-year experimental period each with a duration of the order of 3-6 h. It is notable that high sediment loads were associated with high flow volumes which were effectively the result of the catchment characteristics and incident rainfall causing the flood events in the respective catchments. A large percentage of the annual sediment yield from a catchment is transported by the ephemeral streams during a small number of flood events. The correct determination of the total sediment yield from any of the flood events depends entirely on the accuracy of the measurements.The understanding of run-off and sediment loss for the representative catchments aims at assisting planning, management and control of water and land resources for sustainable development in the semi-arid parts of the tropics. The sediment rates reveal the degradation of catchments which have repercussions on the crop and pasture production and this has a bearing on the soil and water conservation programmes in the delicate ecological balance of the semi-arid areas. Further, these rates will determine the lifespan of the reservoirs planned for the dry river valleys (ephemeral streams) and existing ones which serve livestock and domestic needs. These occasionally will require costly rehabilitation and scooping to increase effective storage unless conservation measures are taken, and these measures are bound to vary from place to place as per the representative catchments output.


Benzene and childhood acute leukemia in Oklahoma.
Although childhood cancer is a leading cause of childhood mortality in the US, evidence regarding the etiology is lacking. The goal of this study was to evaluate the association between benzene, a known carcinogen, and childhood acute leukemia. We conducted a case-control study including cases diagnosed with acute leukemia between 1997 and 2012 (n = 307) from the Oklahoma Central Cancer Registry and controls matched on week of birth from birth certificates (n = 1013). We used conditional logistic regression to evaluate the association between benzene, measured with the 2005 National-Scale Air Toxics Assessment (NATA) at census tract of the birth residence, and childhood acute leukemia. We observed no differences in benzene exposure overall between cases and controls. However, when stratified by year of birth, cases born from 2005 to 2010 had a three-fold increased unadjusted odds of elevated exposure compared to controls born in this same time period (4th Quartile OR: 3.53, 95% CI: 1.35, 9.27). Furthermore, the estimates for children with acute myeloid leukemia (AML) were stronger than those with acute lymphoid leukemia, though not statistically significant. While we did not observe an association between benzene and childhood leukemia overall, our results suggest that acute leukemia is associated with increased benzene exposure among more recent births, and children with AML may have increased benzene exposure at birth. Using the NATA estimates allowed us to assess a specific pollutant at the census tract level, providing an advantage over monitor or point source data. Our study, however, cannot rule out the possibility that benzene may be a marker of other traffic-related exposures and temporal misclassification may explain the lack of an association among earlier births.


Changes in Alcoholic Beverage Choice and Risky Drinking among Adolescents in Europe 1999-2019.
This paper explores trends in beverage preference in adolescents, identifies related regional differences, and examines cluster differences in key drinking measures. Data were obtained from the European School Survey Project on Alcohol and Other Drugs (ESPAD), covering 24 European countries between 1999 and 2019. Trends in the distribution of alcoholic beverages on the participants' most recent drinking occasion were analysed by sex and country using fractional multinomial logit regression. Clusters of countries based on trends and predicted beverage proportions were compared regarding the prevalence of drinkers, mean alcohol volume and prevalence of heavy drinking. Four distinct clusters each among girls and boys emerged. Among girls, there was not one type of beverage that was preferred across clusters, but the proportion of cider/alcopops strongly increased over time in most clusters. Among boys, the proportion of beer decreased, but was dominant across time in all clusters. Only northern European countries formed a geographically defined region with the highest prevalence of heavy drinking and average alcohol volume in both genders. Adolescent beverage preferences are associated with mean alcohol volume and heavy drinking at a country-level. Future approaches to drinking cultures need to take subpopulations such as adolescents into account.


Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.
The homodimeric PolG2 accessory subunit of the mitochondrial DNA polymerase gamma (Pol γ) enhances DNA binding and processive DNA synthesis by the PolG catalytic subunit. PolG2 also directly binds DNA, although the underlying molecular basis and functional significance are unknown. Here, data from Atomic Force Microscopy (AFM) and X-ray structures of PolG2-DNA complexes define dimeric and hexameric PolG2 DNA binding modes. Targeted disruption of PolG2 DNA-binding interfaces impairs processive DNA synthesis without diminishing Pol γ subunit affinities. In addition, a structure-specific DNA-binding role for PolG2 oligomers is supported by X-ray structures and AFM showing that oligomeric PolG2 localizes to DNA crossings and targets forked DNA structures resembling the mitochondrial D-loop. Overall, data indicate that PolG2 DNA binding has both PolG-dependent and -independent functions in mitochondrial DNA replication and maintenance, which provide new insight into molecular defects associated with PolG2 disruption in mitochondrial disease.


Simultaneous non-covalent bi-functionalization of 1T-MoS2 ruled by electrostatic interactions: towards multi-responsive materials.
Dual functionalization of chemically exfoliated MoS2 has been achieved by exploiting coulombic interactions among positively charged molecules and the negatively charged 2D flakes. The reversibility and kinetics of the process have been studied by spectroscopic tools. The hybrid material has been transferred to various substrates, yielding multifunctional robust flexible films.


A Naturalistic Study of Youth Referred to a Tertiary Care Facility for Acute Hypomanic or Manic Episode.
Bipolar Disorders (BD) in youth are a heterogeneous condition with different phenomenology, patterns of comorbidity and outcomes. Our aim was to explore the effects of gender; age at onset (prepubertal- vs. adolescent-onset) of BD; and elements associated with attention deficit hyperactivity disorder (ADHD) and Substance Use Disorder (SUD) comorbidities, severe suicidal ideation or attempts, and poorer response to pharmacological treatments. 117 youth (69 males and 57 females, age range 7 to 18 years, mean age 14.5 ± 2.6 years) consecutively referred for (hypo)manic episodes according to the Diagnostic and Statistical Manual of Mental Disorders, 54th ed (DSM 5) were included. Gender differences were not evident for any of the selected features. Prepubertal-onset BD was associated with higher rates of ADHD and externalizing disorders. SUD was higher in adolescent-onset BD and was associated with externalizing comorbidities and lower response to treatments. None of the selected measures differentiated patients with or without suicidality. At a 6-month follow up, 51.3% of the patients were responders to treatments, without difference between those receiving and not receiving a psychotherapy. Clinical severity at baseline and comorbidity with Conduct Disorder (CD) and SUD were associated with poorer response. Logistic regression indicated that baseline severity and number of externalizing disorders were associated with a poorer outcome. Disentangling broader clinical conditions in more specific phenotypes can help timely and focused preventative and therapeutic interventions.


Theoretical formulation and analysis of the deterministic dendritic cell algorithm.
As one of the emerging algorithms in the field of artificial immune systems (AIS), the dendritic cell algorithm (DCA) has been successfully applied to a number of challenging real-world problems. However, one criticism is the lack of a formal definition, which could result in ambiguity for understanding the algorithm. Moreover, previous investigations have mainly focused on its empirical aspects. Therefore, it is necessary to provide a formal definition of the algorithm, as well as to perform runtime analyses to reveal its theoretical aspects. In this paper, we define the deterministic version of the DCA, named the dDCA, using set theory and mathematical functions. Runtime analyses of the standard algorithm and the one with additional segmentation are performed. Our analysis suggests that the standard dDCA has a runtime complexity of O(n(2)) for the worst-case scenario, where n is the number of input data instances. The introduction of segmentation changes the algorithm's worst case runtime complexity to O(max(nN,nz)), for DC population size N with size of each segment z. Finally, two runtime variables of the algorithm are formulated based on the input data, to understand its runtime behaviour as guidelines for further development.


Effect of beta2-adrenergic receptor agonists on intercellular adhesion molecule (ICAM)-1, B7, and CD40 expression in mixed lymphocyte reaction.
The plasma interleukin (IL)-18 level is elevated in acute rejection after organ transplantation. Although beta2-adrenergic receptor (AR) agonists suppress the rejection of organ and tissue transplants, little is known about their action mechanisms. We examined the effects of endogenous catecholamines and beta2-AR agonists on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) in human mixed lymphocyte reaction (MLR) and in an in vitro model of acute rejection in the presence or absence of IL-18. ICAM-1, B7.1 B7.2, CD40, and CD40L expression on monocytes was measured by flow cytometry, and the production of interferon (IFN)-gamma and IL-12 was determined by enzyme-linked immunosorbent assay. Lymphocytes proliferation in MLR was measured by [3H]-thymidine uptake. The relevant AR subtypes were characterized using subtype-selective agonists and antagonists. beta2-AR agonists inhibited the expression of ICAM-1 and CD40 during MLR in the absence of IL-18. Among IL-18-induced expression of ICAM-1, B7.1, B7.2, CD40, and CD40L, beta2-AR agonists inhibited ICAM-1 and CD40 expression. beta2-AR agonists prevented the production of IFN-gamma and IL-12 in the presence of IL-18 but had no effect in the absence of IL-18. beta2-AR agonists inhibited lymphocyte proliferation in IL-18-treated MLR. We found that beta2-AR agonists strongly inhibited the expression of ICAM-1 and CD40, irrespective of the presence or absence of IL-18, which is different from that of histamine and prostaglandin E2.


Orientation saliency without visual cortex and target selection in archer fish.
Our visual attention is attracted by salient stimuli in our environment and affected by primitive features such as orientation, color, and motion. Perceptual saliency due to orientation contrast has been extensively demonstrated in behavioral experiments with humans and other primates and is believed to be facilitated by the functional organization of the primary visual cortex. In behavioral experiments with the archer fish, a proficient hunter with remarkable visual abilities, we found an orientation saliency effect similar to that observed in human subjects. Given the enormous evolutionary distance between humans and archer fish, our findings suggest that orientation-based saliency constitutes a fundamental building block for efficient visual information processing.


Simple and rapid CD4 testing based on large-field imaging system composed of microcavity array and two-dimensional photosensor.
This study presents a novel method for CD4 testing based on one-shot large-field imaging. The large-field imaging system was fabricated by a microcavity array and a two-dimensional (2D) photosensor within the desk-top-sized instrument. The microcavity array was employed to separate leukocytes from whole blood based on differences in the size of leukocytes and other blood cells. The large-field imaging system with lower side irradiation enabled acquisition of cell signatures with high signal-to-noise ratio, because the metallic substrate of the microcavity array obstructed excessive excitation light. In this setting, dual-color imaging of CD4(+) and CD8(+) T cells was achieved within the entire image area (64 mm(2)) in 2s. The practical performance of the large-field imaging system was demonstrated by determining the CD4/CD8 ratio in a few microliter of control whole blood as small as those obtained by a finger prick. The CD4/CD8 ratios measured using the large-field imaging system correlated well with those measured by microscopic analysis. These results indicate that our proposed system provides a simple and rapid CD4 testing for the application of HIV/AIDS treatment.


ING5 is a Tip60 cofactor that acetylates p53 in response to DNA damage.
Posttranslational modification of p53 is a critical event in regulating the expression of its target genes. p53 is acetylated at lysine 120 (K120) by acetyltranferases Tip60 (KAT5) and hMOF (KAT8) in response to DNA damage. Identification of cofactors for these two enzymes will shed light on the mechanism by which cells make a choice between cell-cycle arrest and apoptosis. It has been reported that ING5, a member of the inhibitor of growth (ING) family, is involved in p53-dependent pathways, but its exact role is unknown. In this study, we found that ING5 expression was significantly increased and that ING5 assisted Tip60, but not hMOF, in acetylating p53 at K120 in response to DNA damage. ING5 had no effect on acetylation of p53 at K373/382, but it formed a complex with p53 and Tip60. ING5 was required for acetylation of p53 at K120, and p53 acetylated at K120 subsequently bound to the promoters of its target apoptotic genes, BAX and GADD45, to promote their expression and lead to apoptosis. Mutation of K120 to K120R abolished the effects of ING5 on p53-induced gene expression. Thus, we conclude that ING5 functions as a cofactor of Tip60 in the acetylation of p53 at K120 in response to DNA damage.


Tuning reactivity layer-by-layer: formic acid activation on Ag/Pd(111).
The potential for tuning the electronic structure of materials to control reactivity and selectivity in heterogenous catalysis has driven interest in ultrathin metal films which may differ from their bulk form. Herein, a 1-atomic layer Ag film on Pd(111) (Ag/Pd(111)) is demonstrated to have dramatically different reactivity towards formic acid compared to bulk Ag. Formic acid decomposition is of interest as a source of H2 for fuel cell applications and modification of Pd by Ag reduces poisoning by CO and increases the selectivity for H2 formation. Formic acid reacts below room temperature on the 1-atomic layer Ag film, whereas no reaction occurs on pristine bulk Ag. Notably, 2 monolayer films of Ag again become unreactive towards formic acid, indicating a reversion to bulk behavior. A combination of infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) was used to establish that the Ag monolayer is continuous and electronically modified compared to bulk Ag. The work establishes a demonstration of the altered electronic structure of Ag monolayers on Pd(111) and an associated change in reactivity. The effect on reactivity only persists for the first layer, demonstrating the need for precise control of materials to exploit the modification in electronic properties.


State conversion based on terahertz plasmonics with vanadium dioxide coating controlled by optical pumping.
The state conversion and terahertz (THz) wave modulation based on a plasmonic device composed of silicon column arrays with vanadium dioxide (VO2) coating were experimentally demonstrated. For double 45° tilted optical pumping, a state conversion from dielectric photonic crystal (PC) to metallic PC was demonstrated due to the insulator-metal transition (IMT) of VO2 with the pump power increasing. In this process, a broadband intensity modulation with 70% modulation depth was achieved. Furthermore, for normally incident optical pumping, another state conversion from dielectric PC to plasmonic device was also demonstrated due to the partial IMT of VO2, and the out of plane PC resonance gradually changed to be plasmonic resonances. This device and its modulation scheme will be of great significance for potential THz applications.


Hierarchy, Not Lexical Regularity, Modulates Low-Frequency Neural Synchrony During Language Comprehension.
Neural responses appear to synchronize with sentence structure. However, researchers have debated whether this response in the delta band (0.5-3 Hz) really reflects hierarchical information or simply lexical regularities. Computational simulations in which sentences are represented simply as sequences of high-dimensional numeric vectors that encode lexical information seem to give rise to power spectra similar to those observed for sentence synchronization, suggesting that sentence-level cortical tracking findings may reflect sequential lexical or part-of-speech information, and not necessarily hierarchical syntactic information. Using electroencephalography (EEG) data and the frequency-tagging paradigm, we develop a novel experimental condition to tease apart the predictions of the lexical and the hierarchical accounts of the attested low-frequency synchronization. Under a lexical model, synchronization should be observed even when words are reversed within their phrases (e.g., "sheep white grass eat" instead of "white sheep eat grass"), because the same lexical items are preserved at the same regular intervals. Critically, such stimuli are not syntactically well-formed; thus a hierarchical model does not predict synchronization of phrase- and sentence-level structure in the reversed phrase condition. Computational simulations confirm these diverging predictions. EEG data from N = 31 native speakers of Mandarin show robust delta synchronization to syntactically well-formed isochronous speech. Importantly, no such pattern is observed for reversed phrases, consistent with the hierarchical, but not the lexical, accounts.


Depression and cerebrovascular disease: could vortioxetine represent a valid treatment option?
Depression and cerebrovascular atherosclerosis often occur in comorbidity showing neuropsychological impairment and poor response to antidepressant treatment. Objective is to evaluate if new antidepressant vortioxetine may be a potential treatment option. Mechanism of Action : Vortioxetine has 5-HT3, 5-HT7 and 5-HT1D antagonists, 5-HT1B partial agonist and a 5-HT1A agonist and serotonin transporter inhibitor property. Efficacy and safety in Major Depressive Disorders and in cognitive impairment : The majority of trials (one of them in older people) showed efficacy for vortioxetine against placebo and no differences against other active treatments. The Adverse Effects ranged from 15.8% more to 10.8% less than placebo. In the elderly, only nausea was found higher than placebo. Effects on arterial blood pressure and cardiac parameters including the ECG-QT segment were similar to placebo. Elderly depressive patients on vortioxetine showed improvement versus placebo and other active comparators in Auditory Verbal Learning Test and Digit Symbol Substitution Test scores. The inclusion criteria admitted cases with middle cerebrovascular disease. Conclusion : The mechanism of action, the efficacy on depression and safety profile and early data on cognitive impairment make Vortioxetine a strong candidate for use in depression associated with cerebrovascular disease. This information must be supported by future randomized controlled trials.


[Functional analysis of a chitinase gene PnCHI1 from Panax notoginseng].
Chitinases, a glycosidase enzyme that hydrolyzes chitin to N-acetylglucosamine, are widely found in plant cells, and they are an important part of plant antifungal defense system. The function of a Panax notoginseng chitinase gene PnCHI1 was characterized in this paper. Expression vector of PnCHI1 was constructed and transiently expressed in onion epidermal cells, and laser scanning confocal microscopy demonstrated that PnCHI1 was localized in the cell wall. Prokaryotic expression vector of PnCHI1 was also constructed, and recombinant protein of PnCHI1 was induced and purified. In vitro antibacterial assay showed that recombinant PnCHI1 protein had strong inhibitory activity on the mycelium growth of Fusarium solani, F. oxysporum and F. verticillioide. The function of PnCHI1 was further verified by reverse genetics. PnCHI1 expression vector was transferred into tobacco by Agrobacterium tumefaciens and expression of PnCHI1 was confirmed by qRT-PCR. It was found by leaf inoculation experiment that resistance of transgenic tobacco to F. solani was significantly increased. It is conclnded that: PnCHI1 is a chitinase localized in the cell wall, which inhibits several fungi which cause the root rot disease of P. notoginseng. Overexpression of this chitinase gene in tobacco greatly increased resistance to F. solani. PnCHI1 may be an important resistance gene in P. notoginseng that participates in the defense against root rot disease.


PP2A-associated tau hyperphosphorylation was involved in sevoflurane induced neonatal neurotoxicity.
The effects of sevoflurane anesthesia on childhood neurodevelopment and adult brain function have attracted increasing scientific attentions. However, the exact mechanisms underlying hyperphosphorylation of tau protein in sevoflurane induced abnormalities in central nervous system (CNS) development, particularly in the hippocampus, have not been fully determined. We utilized molecular biological and behavioral approaches to compare the changes in cognitive function in mice exposed to repeated sevoflurane during the neonatal stage, and to assess whether PP2A-associated tau hyperphosphorylation is involved in sevoflurane induced neonatal neurotoxicity. We reported that mice anesthetized with repeated sevoflurane during the neonatal period caused cognitive dysfunction during the adulthood. More importantly, we found that hyperphosphorylation of tau protein and decreased level of protein phosphatase 2A (PP2A) were detected in the hippocampus of mice after neonatal exposure of sevoflurane. Meanwhile, GSK-3β activity was found to be increased with repeated sevoflurane exposure, but not for more than 2 weeks. Our results suggest that PP2A-associated hyperphosphorylation of tau protein might contribute to sevoflurane induced developmental neurotoxicity. These findings could provide a theoretical basis for the safely usage of sevoflurane in pediatric surgeries, and offer a valuable reference and potential therapeutic targets for the development of neuroprotective drugs.


Properties of Escherichia coli mutants deficient in enzymes of glycolysis.
Physiological properties of mutants of Escherichia coli defective in glyceraldehyde 3-phosphate dehydrogenase, glycerate 3-phosphate kinase, or enolase are described. Introduction of a lesion in any one of the reversible steps catalyzed by these enzymes impaired both the glycolytic and gluconeogenic capabilities of the cell and generated an obligatory requirement for a source of carbon above the block (gluconeogenic) and one below (oxidative). A mixture of glycerol and succinate supported the growth of these mutants. Mutants lacking glyceraldehyde 3-phosphate dehydrogenase and glycerate 3-phosphate kinase could grow also on glycerol and glyceric acid, and enolase mutants could grow on glycerate and succinate, whereas double mutants lacking the kinase and enolase required l-serine in addition to glycerol and succinate. Titration of cell yield with limiting amounts of glycerol with Casamino Acids in excess, or vice versa, showed the gluconeogenic requirement of a growing culture of E. coli to be one-twentieth of its total catabolic and anabolic needs. Sugars and their derivatives inhibited growth of these mutants on otherwise permissive media. The mutants accumulated glycolytic intermediates above the blocked enzyme on addition of glucose or glycerol to resting cultures. Glucose inhibited growth and induced lysis. These effects could be substantially overcome by increasing the osmotic strength of the growth medium and, in addition, including 5 mM cyclic adenosine 3',5'-monophosphate therein. This substance countered to a large extent the severe repression of beta-galactosidase synthesis that glucose caused in these mutants.


Copy number variants within AZF region of Y chromosome and their association with idiopathic male infertility in Serbian population.
Results of numerous studies gave contradictory conclusions when analysing associations between copy number variants (CNVs) within the azoospermia factor (AZF) locus of the Y chromosome and idiopathic male infertility. The aim of this study was to identify the presence and possible association of CNVs in the AZF region of Y chromosome with idiopathic male infertility in the Serbian population. Using the multiplex ligation-dependent probe amplification technique, we were able to detect CNVs in 24 of 105 (22.86%) infertile men and in 11 of 112 (9.82%) fertile controls. The results of Fisher's exact test showed a statistically significant difference between cases and controls after merging g(reen)-r(ed)/g(reen)-r(ed) and b(lue)2/b(lue)3 partial deletions identified in the AZFc region (p = 0.024). At the same time, we observed a trend towards statistical significance for a deletion among gr/gr amplicons (p = 0.053). In addition to these, we identified a novel complex CNV involving inversion of r2/r3 amplicons, followed by b2/b3 duplication and b3/b4 deletion, respectively. Additional analyses on a larger study group would be necessary to draw meaningful conclusions about associations among CNVs that presented with higher frequency in the infertile men than the fertile controls.


[Successful treatment of eruptive xanthomatosis with the antilipemic agents acipimox].
A 51-year-old male patient with histologically confirmed eruptive xanthomatosis is presented. Routine and special laboratory examinations showed complex disturbances of carbohydrate and lipid metabolism, the latter taking the form of classic hyperlipoproteinaemia type IV. Combined oral antilipaemic drugs including acipimox (methylpyrazine carboxylic acid analogue of nicotinic acid) and a low-fat diet resulted in regression of the skin symptoms and normalization of the serum lipid levels.


Production of Modified Nucleosides in a Continuous Enzyme Membrane Reactor.
Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocatalysts until their full inactivation, they offer a valuable alternative to batch enzymatic reactions with freely dissolved enzymes. In EMRs, the enzymes are retained in the reactor by a suitable membrane. Immobilization on carrier materials, and the associated losses in enzyme activity, can thus be avoided. Therefore, we validated the applicability of EMRs for the synthesis of natural and dihalogenated nucleosides, using one-pot transglycosylation reactions. Over a period of 55 days, 2'-deoxyadenosine was produced continuously, with a product yield >90%. The dihalogenated nucleoside analogues 2,6-dichloropurine-2'-deoxyribonucleoside and 6-chloro-2-fluoro-2'-deoxyribonucleoside were also produced, with high conversion, but for shorter operation times, of 14 and 5.5 days, respectively. The EMR performed with specific productivities comparable to batch reactions. However, in the EMR, 220, 40, and 9 times more product per enzymatic unit was produced, for 2'-deoxyadenosine, 2,6-dichloropurine-2'-deoxyribonucleoside, and 6-chloro-2-fluoro-2'-deoxyribonucleoside, respectively. The application of the EMR using freely dissolved enzymes, facilitates a continuous process with integrated biocatalyst separation, which reduces the overall cost of the biocatalyst and enhances the downstream processing of nucleoside production.


Practical guidelines to interpret plasma concentrations of antiretroviral drugs.
Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice. In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication. In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.


VideoModerator: A Risk-aware Framework for Multimodal Video Moderation in E-Commerce.
Video moderation, which refers to remove deviant or explicit content from e-commerce livestreams, has become prevalent owing to social and engaging features. However, this task is tedious and time consuming due to the difficulties associated with watching and reviewing multimodal video content, including video frames and audio clips. To ensure effective video moderation, we propose VideoModerator, a risk-aware framework that seamlessly integrates human knowledge with machine insights. This framework incorporates a set of advanced machine learning models to extract the risk-aware features from multimodal video content and discover potentially deviant videos. Moreover, this framework introduces an interactive visualization interface with three views, namely, a video view, a frame view, and an audio view. In the video view, we adopt a segmented timeline and highlight high-risk periods that may contain deviant information. In the frame view, we present a novel visual summarization method that combines risk-aware features and video context to enable quick video navigation. In the audio view, we employ a storyline-based design to provide a multi-faceted overview which can be used to explore audio content. Furthermore, we report the usage of VideoModerator through a case scenario and conduct experiments and a controlled user study to validate its effectiveness.


Safety and effectiveness of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study.
The aim of this study was to further assess the long-term safety and effectiveness of open-label topiramate therapy in subjects with moderately to severely painful diabetic peripheral neuropathy (DPN). Adults aged 18 to 75 years received open-label topiramate (25-600 mg/d for 26 weeks) in an extension of a previously published randomized, double-blind trial comparing topiramate with placebo. Safety analyses included adverse event (AE) reports and clinical laboratory tests. Metabolic end points included body weight and glycosylated hemoglobin (HbA(1c)). Effectiveness analyses included a 100-mm pain visual analog (PVA) scale, worst and current pain severity, and sleep disruption. Two hundred five subjects participated in this open-label extension study (118 formerly treated with topiramate and 87 who formerly received placebo). The groups did not differ in baseline demographics or disease characteristics. One hundred twenty-four (60.5%) subjects (68.6% of former topiramate recipients and 49.4% of former placebo recipients) completed the extension study; the most common reason for discontinuation was an AE (27.3% of subjects). AEs among subjects who received > or =1 dose of topiramate (n = 298) included upper respiratory tract infection (16.1%), anorexia (15.1%), diarrhea (12.8%), nausea (12.8%), paresthesia (10.7%), and headache (10.1%). Baseline pain scores were lower in those formerly treated with topiramate (n = 117) than in the former placebo group (n = 86) (PVA: 43.3 vs 52.5, P = 0.014; worst pain: 1.9 vs 2.5, P < 0.001; current pain: 1.6 vs 1.9, P = 0.026; sleep disruption: 3.6 vs 4.6, P = 0.021). At the final visit, PVA, current pain, and sleep disruption scores were not significantly different between the former topiramate and former placebo groups, but worst pain differed significantly (1.4 vs 1.8; P = 0.025). Mean weight loss from the start of topiramate therapy was 5.2 and 5.3 kg in the former topiramate and former placebo groups, respectively (P < 0.001 vs baseline). Mean HbA(1c) values before and after topiramate treatment were 7.7% and 7.4%, respectively, in the former topiramate group (P = 0.004 vs baseline), and 7.6% and 7.1%, respectively, in the former placebo group (P < 0.001 vs baseline). Although 39.5% of subjects discontinued, most often due to AEs, the results of this 26-week, open-label extension study with topiramate (up to 600 mg/d) in subjects with moderately to severely painful DPN suggest that pain relief was effective and durable.


Nicotine dependence and its correlates among the adult tobacco users in a slum of Burdwan district, West Bengal, India.
Tobacco kills half of its users, with smoking and smokeless tobacco killing nearly 6 million people worldwide - one death every 6 s in each year. Use of tobacco over time causes a physical and psychological addiction due to the presence of nicotine. To find out the level of nicotine dependence among adult (18 years and above) tobacco users and the factors responsible for it. A cross-sectional community-based study was conducted among 128 current tobacco users in an urban slum of Burdwan District, West Bengal, India. Study tools comprised of predesigned, pretested, semi-structured schedule, containing Fagerström test for nicotine dependence (FTND) questionnaire. Data were collected by interview after getting consent from the participants. Chi-square test, unpaired student t-test, ANOVA, correlation coefficient, and linear regression was calculated. SPSS software (Statistical Package for the Social Sciences Inc, Chicago, IL, USA). was used for analysis. High level of nicotine dependence was maximally seen among increased in age group, prolonged duration of use and daily users. Age, duration of tobacco use and habit of tobacco use had a significant positive correlation with FTND score while starting age of tobacco had a significant negative correlation. Then in multivariable linear regression, starting age of tobacco use, habit of tobacco use and duration of tobacco use emerged as a significant predictor of FTND score and could explain 27.3% of total variation in FTND score. Suitable plan for quitting may be developed based on the FTND score of an individual, the most important determinant of quitting.


Plasma miRNA Biomarkers in Limited Volume Samples for Detection of Early-stage Pancreatic Cancer.
Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE: Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention.


Telehealth as a tool for independent self-management by people living with long term conditions.
Telehealth is seen as a key component of 21st century healthcare, and studies have explored its cost effectiveness and impact on hospital admissions. Research has been carried out into how to best implement it, and the barriers to its adoption. The impact of telehealth on self-management however has been a neglected area. An evaluation of the implementation of a telehealth programme in one area in the South of England found that some patients were using the telehealth equipment provided to enhance their own self management abilities. Whilst the nurses managing the scheme felt that they had an education role they did not involve their patients in setting goals. The patients equally did not feel that were being educated by their nurses. Patients were using the monitoring equipment independently of the nurses and the scheme to support their self-management strategies. Therefore the concept of graduating from telehealth once good self-management is established needs to be rethought. Patients in this study experienced less face to face contact with their nurse, but also reported that they were happy with the changes. This suggests that for some patients the contact with the nurse may well be able to be reduced or withdrawn however removing the monitoring equipment will remove the very tools essential to continued self-management.


Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues.
In previous studies we demonstrated telomerase activity in frozen tissues from BCC and their tumor-free margins by the PCR ELISA. In this study we examined in the same frozen sections immunohistochemical presence of hTERT in the nucleus. After fixation in acetone and methanol followed by steaming we used for visualization the antigen-antibody reactions by APAAP. This was the best method of preparation of the frozen sections in our preliminary hTERT-study with squamous cell carcinomas. This study was supplemented with antibodies against Ki-67, nucleolin, common leucocyte antigen CD45 and mutated p53. The immunoreactive scores were determined and included the comparison with telomerase activity. The investigation of hTERT expression was performed in the tissues of 41 patients with BCC and control tissues of 14 patients without tumor. Eleven commercial antibodies were used for a nuclear staining of hTERT expression. With the anti-hTERT antibodies we looked for both satisfactory distribution and intensity of immunohistochemical labeling in the carcinomas and in the squamous epithelia of the tumor centers, of the tumor-free margins and of the control tissues. The hTERT expression in the BCC was distributed heterogeneously. The score values established by the anti-hTERT antibodies used were variably or significantly increased. In the stroma they tended to be negative, so we disregarded stroma hTERT. Proof of hTERT did not differ uniformly from telomerase activity. We compared the high with the lower median hTERT values in the Kaplan-Meier curve. Patients with lower hTERT scores in the center or tumor margin as shown by some of the antibodies suffered relapse earlier. Finally, we compared the hTERT expression in BCC tissues with the hTERT scores in HNSCC tissues from our previous study. Only one anti-hTERT antibody (our Ab 7) yielded significantly higher scores in BCC than in HNSCC.


Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort.
Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1β overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1β monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections. Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects.


The change in initial lung volume during exercise.
The lung volumes from which inhalation and exhalation proceed change during exercise. There have been previous attempts to predict these lung volumes but none have been completely successful. Prediction of initial lung volume is important in the accurate calculation of respiratory power during exercise, especially when the subject is encumbered with respiratory protective apparatus and exercising above the anaerobic threshold. Although there is no direct work advantage to varying lung volumes at the beginning of inspiration or expiration, such changes appear to be dictated by the asymmetry of lung recoil pressure about the lung relaxation volume. Equalizing inspiratory and expiratory elastic pressures has been found to match available data on lung initial volume.


Bcl-6-dependent risk stratification by nuclear expression of Peli1 in diffuse large B-cell lymphoma.
Background/Aim: Peli1 is an E3 ubiquitin ligase involving lymphomagenesis by lysine 63 ubiquitination-mediated stabilization of Bcl-6 with in diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We categorized nuclear expression of Peli1 according to Bcl-6 status by immunohistochemistry in DLBCL (n=100), and analyzed clinicopathologic association with prognosis. Results: We established Bcl-6/Peli1 risk model composed of high risk (Bcl-6+/Peli1+ or Bcl-6-/Peli1-; n=64) and low risk (Bcl-6+/Peli1- or Bcl-6-/Peli1+; n=36). High risk group had more frequent non-GCB subtype (83% vs 64%; p=0.033) and Bcl-6-negativity (69% vs 28%; p<0.001) than low risk group. Univariate survival analysis for progression-free survival (PFS) and overall survival (OS) revealed Bcl-6/Peli1 risk group (p=0.026 and p=0.021) and other conventional variables including international prognostic index (IPI), stage, ECOG performance status, number of extranodal sites were significant prognostic factors, along with B symptoms for OS. In multivariate analysis for PFS, Bcl-6/Peli1 risk group (p=0.032; HR=3.29), IPI (p=0.013; HR=3.39) and ECOG PS (p=0.035; HR=3.08) were independent prognostic factors. In multivariate analysis for OS, Bcl-6/Peli1 risk group (p=0.048; HR=7.87) and IPI (p=0.001; HR=12.15) were associated with prognosis. Conclusions: DLBCL had distinctive risk groups according to pairs of nuclear Peli1 and Bcl-6 expression. These results suggest the potential role of Peli1 and Bcl-6 in risk assessment in DLBCL.


Isolation and purification of CD14-negative mucosal macrophages from normal human small intestine.
Mucosal macrophages play a fundamental role in the regulation of immunological events and inflammation in the small intestine. Because no information is available on normal small intestinal macrophages, we developed a technique for the isolation and purification of jejunal lamina propria macrophages in order to study their phenotype and activity. From sections of normal human jejunum, lamina propria mononuclear cells were isolated by neutral protease digestion and then subjected to counterflow centrifugal elutriation to purify the macrophages. The cells isolated by this procedure contained < 1% CD3+ lymphocytes and displayed the size distribution, morphological features, ultrastructure and phagocytic activity of mononuclear phagocytes. In contrast to blood monocytes, however, mucosal macrophages from the jejunum did not exhibit adherence properties or express CD14, a receptor for the lipopolysaccharide-binding protein. The purification of large numbers of lamina propria macrophages by this procedure offers the opportunity to define the role of this cell in the physiological inflammation characteristic of normal intestinal mucosa and the pathological inflammation associated with small intestinal diseases.


Visualization of Polymer Deformation Using Microcapsules Filled with Charge-Transfer Complex Precursors.
The visualization of polymer deformation using microcapsules filled with charge-transfer complex precursors is reported. Poly(urea-formaldehyde) microcapsules filled with toluene and either hexamethylbenzene as donor or chloranil as acceptor were prepared by in situ polymerization of an oil-in-water emulsion. The resulting microcapsules were incorporated in a poly(dimethylsiloxane) matrix by dispersing them in the monomer and subsequent curing. The microcapsules were shown to rupture when the polymer was placed under mechanical forces (i.e., tensile and compression) such that the donor and the acceptor are released into the polymeric matrix, where their combination to a charge-transfer complex results in a pronounced yellow-to-red color change. The factors influencing the extent of the color change (composition and mechanical strain) were investigated and a deformation threshold seems to be present. The new damage-sensing materials may be useful for a range of applications and the general concept applied seems to be readily applicable to other host polymers.


Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy.
Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition of peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface. However, because natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. In this study, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with those of their wild-type progenitors. Additionally, we performed molecular dynamics simulations to better understand the energetic mechanisms driving the affinity enhancements. These data demonstrate that supra-physiological binding affinities can be achieved without altering native TCR-pHLA binding modes via relatively subtle modifications to the interface contacts, often driven through the addition of buried hydrophobic residues. Individual energetic components of the TCR-pHLA interaction governing affinity enhancements were distinct and highly variable for each TCR, often resulting from additive, or knock-on, effects beyond the mutated residues. This comprehensive analysis of affinity-enhanced TCRs has important implications for the future rational design of engineered TCRs as efficacious and safe drugs for cancer treatment.


Over-the-counter medications for acute cough in children and adults in ambulatory settings.
Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Many health practitioners recommend non-prescription over-the-counter (OTC) medicines as a first-line treatment for cough, but there is little evidence as to whether these drugs are effective. To assess the effects of oral over-the-counter cough preparations for acute cough. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004); MEDLINE (January 1966 to June Week 3, 2004); EMBASE (January 1990 to March 2004); and the UK Department of Health National Research Register (December 2003, http://www.update-software.com/National/nrr-frame.html). We also searched personal collections of references and reference lists of articles. We wrote to study investigators and pharmaceutical companies for information on further published or unpublished studies. There were no constraints based on language or publication status. Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in ambulatory settings. We considered all cough outcomes (such as frequency and severity, continuous and categorical data, using different ways of measurement). The second outcomes of interest were adverse effects. Two investigators screened potentially relevant citations independently. Any differences at any stage of the review were resolved by discussion. We also extracted data and assessed the quality of studies independently. We contacted investigators for additional information and performed quantitative analysis when appropriate data were available. Twenty four trials (17 in adults, seven in children) involving 3,392 people (2,876 adults and 516 children) were included. RESULTS OF STUDIES IN ADULTS: 1. Antitussives: Six trials compared antitussives with placebo. Codeine was no more effective than placebo in reducing cough symptoms. Two studies favoured dextromethorphan over placebo, whereas a third did not show an effect. Moguisteine was no more effective than placebo apart from a reduction of cough in a subgroup of participants with more severe night cough. 2. Expectorants: Two trials compared guaifenesin with placebo. In the larger study, 75 per cent of participants taking guaifenesin stated that the medicine was helpful compared to 31 per cent in the control group. In the second study, both groups showed improvement with respect to cough frequency and severity, with no statistically significant differences between groups. 3. Mucolytics: One trial compared a mucolytic with placebo. Active treatment reduced cough frequency and symptom scores on day four and eight. 4. Antihistamine-decongestant combinations: Two studies compared antihistamine-decongestant combinations with placebo. Antihistamine-decongestants were significantly more effective than placebo in one of the studies, whereas the other did not show any difference between the study groups. 5. Other drug combinations: Three studies compared combinations of drugs other than antihistamine-decongestant with placebo. Two studies were effective in reducing cough symptoms, and one study showed relief at night but not during the day. 6. Antihistamines: Three trials compared antihistamines with placebo. Antihistamines were no more effective than placebo in relieving cough symptoms. RESULTS OF STUDIES IN CHILDREN: 1. Antitussives: Antitussives were no more effective than placebo (one study) 2. Expectorants: No studies using expectorants met our inclusion criteria. 3. Mucolytics: The results of one trial favoured active treatment over placebo from day four until day 10. 4. Antihistamine-decongestant combinations: Two studies showed no difference between antihistamine-decongestant combinations and placebo. 5. Other drug combinations: One trial tested two paediatric cough syrups. Compared to placebo, both preparations showed a 'satisfactory response' in 46 per cent and 56 per cent of children compared to 21 per cent of children in the placebo group. One study compared an antitussive/bronchodilator combination in children, which showed no difference between the treatment groups. 6. Antihistamines: In one trial that tested antihistamines active treatment was no more effective than placebo. There is no good evidence for or against the effectiveness of OTC medicines in acute cough. The results of this review have to be interpreted with caution due to differences in study designs, populations, interventions and outcomes between studies. The numbers of studies in each group were small, and studies often showed conflicting results. Effect sizes in many studies were unclear and it is questionable as to whether all of the positive results are clinically relevant. More evidence about the effectiveness of OTC cough preparations would be helpful, as identification of effective self-care treatments may help reduce the burden of days lost at work due to acute cough as well as the number of consultations in primary care. Identification of ineffective preparations could avoid costs for consumers and health care providers.


Crystallization and preliminary X-ray diffraction of the Munc18c-syntaxin4 (1-29) complex.
The production of diffraction-quality crystals of Munc18c, a protein involved in regulating vesicular exocytosis in mammals, is reported. The diffraction resolution of Munc18c crystals was optimized by (i) cocrystallizing with a peptide fragment of the Munc18c functional binding partner syntaxin4, (ii) using nanolitre free-interface diffusion crystallization-screening chips and microlitre hanging-drop vapour diffusion and (iii) applying a post-crystallization dehydration treatment. Crystals belonging to the cubic space group P2(1)3, with unit-cell parameters a = b = c = 170.8 A, alpha = beta = gamma = 90 degrees , were generated that diffract to 3.7 A resolution on a laboratory X-ray source.


Codon-Restrained Method for Both Eliminating and Creating Intragenic Bacterial Promoters.
Future applications of synthetic biology will require refactored genetic sequences devoid of internal regulatory elements within coding sequences. These regulatory elements include cryptic and intragenic promoters, which may constitute up to a third of the predicted Escherichia coli promoters. The promoter activity is dependent on the structural interaction of core bases with a σ factor. Rational engineering can be used to alter key promoter element nucleotides interacting with σ factors and eliminate downstream transcriptional activity. In this paper, we present codon-restrained promoter silencing (CORPSE), a system for removing intragenic promoters. CORPSE exploits the DNA-σ factor structural relationship to disrupt σ70 promoters embedded within gene coding sequences with a minimum of synonymous codon changes. Additionally, we present an inverted CORPSE system, iCORPSE, which can create highly active promoters within a gene sequence while not perturbing the function of the modified gene.


Statistical assessment of biosimilar products.
Biological products or medicines are therapeutic agents that are produced using a living system or organism. Access to these life-saving biological products is limited because of their expensive costs. Patents on the early biological products will soon expire in the next few years. This allows other biopharmaceutical/biotech companies to manufacture the generic versions of the biological products, which are referred to as follow-on biological products by the U.S. Food and Drug Administration (FDA) or as biosimilar medicinal products by the European Medicine Agency (EMEA) of the European Union (EU). Competition of cost-effective follow-on biological products with equivalent efficacy and safety can cut down the costs and hence increase patients' access to the much-needed biological pharmaceuticals. Unlike for the conventional pharmaceuticals of small molecules, the complexity and heterogeneity of the molecular structure, complicated manufacturing process, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence (similarity) between the biosimilar products and their corresponding innovator product a great challenge for both the scientific community and regulatory agencies. In this paper, we provide an overview of the current regulatory requirements for approval of biosimilar products. A review of current criteria for evaluation of bioequivalence for the traditional chemical generic products is provided. A detailed description of the differences between the biosimilar and chemical generic products is given with respect to size and structure, immunogenicity, product quality attributed, and manufacturing processes. In addition, statistical considerations including design criteria, fundamental biosimilar assumptions, and statistical methods are proposed. The possibility of using genomic data in evaluation of biosimilar products is also explored.


Microbiology of acute otitis media recently treated with aminopenicillins.
Sparse recent data are available in the United States regarding the pathogens of acute otitis media (AOM) most likely to be recovered from children recently treated with the two most frequently prescribed antibiotics, amoxicillin or amoxicillin/clavulanate (AMC). Of the 704 rural Kentucky children with culture-positive AOM who underwent a single tympanocentesis or culture of otorrhea between 1992 and 1998, 96 pathogens were recovered from 90 children during therapy or within 7 days posttherapy with an aminopenicillin. Identification and susceptibility testing of AOM pathogens were performed by routine National Committee for Clinical Laboratory Standards methods. Pathogens recovered from children with AOM recently treated (0 to 7 days) with amoxicillin (n = 38) and AMC (n = 58), respectively, were as follows: Haemophilus influenzae (beta-lactamase-negative), 16 and 29%; H. influenzae (beta-lactamase-positive), 11 and 22%; penicillin-susceptible Streptococcus pneumoniae, 26 and 12%; intermediately penicillin-nonsusceptible S. pneumoniae (PNSP), 20 and 10%; resistant PNSP 13 and 17%; Moraxella catarrhalis (beta-lactamase-positive), 13 and 7%; and Streptococcus pyogenes, 3 and 2%. H. influenzae was also isolated from 8 (75%) of 12 children treated with high dose AMC ( approximately 80 mg/kg/day amoxicillin component). Significantly fewer children recently treated with amoxicillin were otitis-prone than those given AMC (24% vs. 74%, P < 0.0001). The predominant pathogen recovered from children with AOM recently treated with amoxicillin was S. pneumoniae (59%) rather than beta-lactamase-producing organisms (24%). H. influenzae was the predominant (51%) pathogen, rather than PNSP (27%), recovered from children recently treated with AMC.


Hebbian plasticity in parallel synaptic pathways: A circuit mechanism for systems memory consolidation.
Systems memory consolidation involves the transfer of memories across brain regions and the transformation of memory content. For example, declarative memories that transiently depend on the hippocampal formation are transformed into long-term memory traces in neocortical networks, and procedural memories are transformed within cortico-striatal networks. These consolidation processes are thought to rely on replay and repetition of recently acquired memories, but the cellular and network mechanisms that mediate the changes of memories are poorly understood. Here, we suggest that systems memory consolidation could arise from Hebbian plasticity in networks with parallel synaptic pathways-two ubiquitous features of neural circuits in the brain. We explore this hypothesis in the context of hippocampus-dependent memories. Using computational models and mathematical analyses, we illustrate how memories are transferred across circuits and discuss why their representations could change. The analyses suggest that Hebbian plasticity mediates consolidation by transferring a linear approximation of a previously acquired memory into a parallel pathway. Our modelling results are further in quantitative agreement with lesion studies in rodents. Moreover, a hierarchical iteration of the mechanism yields power-law forgetting-as observed in psychophysical studies in humans. The predicted circuit mechanism thus bridges spatial scales from single cells to cortical areas and time scales from milliseconds to years.


The Molecular Basis for Erns Dimerization in Classical Swine Fever Virus.
The pestivirus classical swine fever virus (CSFV) represents one of the most important pathogens of swine. Its virulence is dependent on the RNase activity of the essential structural glycoprotein Erns that uses an amphipathic helix as a membrane anchor and forms homodimers via disulfide bonds employing cysteine 171. Dimerization is not necessary for CSFV viability but for its virulence. Mutant Erns proteins lacking cysteine 171 are still able to interact transiently as shown in crosslink experiments. Deletion analysis did not reveal the presence of a primary sequence-defined contact surface essential for dimerization, but indicated a general importance of an intact ectodomain for efficient establishment of dimers. Pseudoreverted viruses reisolated in earlier experiments from pigs with mutations Cys171Ser/Ser209Cys exhibited partially restored virulence and restoration of the ability to form Erns homodimers. Dimer formation was also observed for experimentally mutated proteins, in which other amino acids at different positions of the membrane anchor region of Erns were replaced by cysteine. However, with one exception of two very closely located residues, the formation of disulfide-linked dimers was only observed for cysteine residues located at the same position of the helix.


Effective therapy for poor-prognosis non-Hodgkin's lymphoma with 8 weeks of high-dose-intensity combination chemotherapy.
Despite substantial advances in the treatment of aggressive non-Hodgkin's lymphoma, therapeutic results with conventional regimens remain poor in some subsets of patients. In an attempt to improve the prognosis of such patients we used an 8-week, multidrug chemotherapy regimen of high dose-intensity. Between April 1986 and April 1991, 70 patients with advanced intermediate- or high-grade non-Hodgkin's lymphoma were treated. The median age was 41 years (range, 18 to 69). Fifty-one patients (73%) had stage IV disease; 37 (53%) were Shipp's category 3; 17 (24%) had small noncleaved-cell lymphoma; 35 (50%) had Eastern Cooperative Oncology Group (ECOG) performance status > or = 2; 24 (34%) had two or more extranodal sites involved; and 17 (24%) had bone marrow involvement. The 8-week regimen included cyclophosphamide, etoposide, doxorubicin, vincristine, bleomycin, methotrexate with leucovorin rescue, and prednisone. Sixty-two of 70 patients completed the regimen as planned. Fifty-seven patients (81%) obtained a complete response (CR) and the actuarial 5-year failure-free survival rate is 52%. Thirty-seven patients remain alive and disease-free a median of 35 months (range, 7 to 68) after therapy. Adverse prognostic factors included age more than 50 years, bone marrow involvement, and serum lactic dehydrogenase (LDH) more than 500 IU/L (normal range, 125 to 250). Myelosuppression was responsible for most of the treatment-related toxicity. Severe leukopenia (< 1,000/microL) occurred in all patients and lasted a median of 9 days. Seven patients (10%) died of myelosuppression-related complications; five of these patients were older than 60 years. This brief but intensive therapy was effective in treating poor-prognosis patients with non-Hodgkin's lymphoma. With this therapy, patients with small noncleaved-cell lymphoma or Shipp's category 3 disease had treatment outcome similar to the group as a whole. This therapy was not well tolerated by patients older than 60 years, and should not be given to this subgroup. Verification of these results in a randomized trial setting is indicated.


Shared decision making does not influence physicians against clinical practice guidelines.
While shared decision making (SDM) and adherence to clinical practice guidelines (CPGs) are important, some believe they are incompatible. This study explored the mutual influence between physicians' intention to engage in SDM and their intention to follow CPGs. Embedded within a clustered randomized trial to assess the impact of training physicians in SDM about using antibiotics to treat acute respiratory tract infections, this study evaluated physicians' intentions to both engage in SDM and follow CPGs. A self-administered questionnaire based on the theory of planned behavior evaluated both behavioral intentions and their respective determinants (attitude, subjective norm and perceived behavioral control) at study entry and exit. We used path analysis to explore the relationships between the intentions. We conducted statistical analyses using the maximum likelihood method and the variance-covariance matrix. Goodness of fit indices encompassed the chi-square statistic, the comparative fit index and the root mean square error of approximation. We analyzed 244 responses at entry and 236 at exit. In the control group, at entry we observed that physicians' intention to engage in SDM (r = 0, t = 0.03) did not affect their intention to follow CPGs; however, their intention to follow CPGs (r = -0.31 t = -2.82) did negatively influence their intention to engage in SDM. At exit, neither behavioral intention influenced the other. In the experimental group, at entry neither behavioral intention influenced the other; at exit, the intention to engage in SDM still did not influence the intention to use CPGs, although the intention to follow CPGs (r = -0.15 t = -2.02) slightly negatively influenced the intention to engage in SDM, but this was not clinically significant. Physicians' intention to engage in SDM does not affect their intention to adopt CPGs even after SDM training. Physicians' intention to adopt CPGs had no clinically significant influence on intention to engage in SDM. ClinicalTrials.gov NCT01116076.


Er:YAG laser or high-speed bur for cavity preparation in adolescents.
The aim was to evaluate the effect on cavity preparation time, the pulse changes and the patient's subjective experience during removal of healthy tooth substance with high-speed bur and Er:YAG laser. Thirty-five (13 male, 22 female) 14-18-year-olds participated. After local anaesthesia, Er:YAG laser and high-speed diamond bur were used for a 2 mm deep cavity preparation on the middle of the buccal surface on contra-lateral healthy maxillary first premolars. The cavity preparation time and the pulse were measured during the treatment. Subjective experience was evaluated using a VAS-scale and a questionnaire. Wilcoxon Signed Rank test and Chi-2-test were used for statistical analyses. The mean (SD) cavity preparation time was 3.7-times longer (p < 0.001) for the laser [59 (41) s] than for the high-speed bur [16 (4) s]. The mean pulse change during preparation differed (p < 0.05) between the bur (+2.2%) and laser (-4.4%). The smell was worse when laser was used (p < 0.01); 65.7% expressed less discomfort and 57.1% experienced a lower sound level when laser was used. Laser was preferred for future treatment in 62.9% of the adolescents. Laser ablation caused unpleasant smell and longer cavity preparation time, but was preferred by a majority of the adolescents.


PTEN Tumor-Suppressor: The Dam of Stemness in Cancer.
PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.


Dopamine-sensitive adenylate cyclase: location in substantia nigra.
A dopamine-sensitive adenylate cyclase with characteristics similar to those measured in the striatum is present in the rat substantia nigra. Destruction of dopamine cell bodies by intranigral 6-hydroxydopamine application failed to abolish the response of nigral adenylate cyclase to dopamine. In contrast, brain hemitransection between the striatum and substantia nigra, or a more circumscribed lesion of striatonigral pathways, abolished the dopamine stimulation of adenylate cyclase in the substantia nigra. These results suggest that dopamine receptors within the substantia nigra are not located on dopamine cell bodies but are associated with a pathway, containing gamma-aminobutyric acid or substance P, which projects from forebrain structures to the substantia nigra.


The Disgust Scale: item analysis, factor structure, and suggestions for refinement.
In the 4 studies presented (N = 1,939), a converging set of analyses was conducted to evaluate the item adequacy, factor structure, reliability, and validity of the Disgust Scale (DS; J. Haidt, C. McCauley, & P. Rozin, 1994). The results suggest that 7 items (i.e., Items 2, 7, 8, 21, 23, 24, and 25) should be considered for removal from the DS. Secondary to removing the items, exploratory and confirmatory factor analyses revealed that the DS taps 3 dimensions of disgust: Core Disgust, Animal Reminder Disgust, and Contamination-Based Disgust. Women scored higher than men on the 3 disgust dimensions. Structural modeling provided support for the specificity of the 3-factor model, as Core Disgust and Contamination-Based Disgust were significantly predictive of obsessive- compulsive disorder (OCD) concerns, whereas Animal Reminder Disgust was not. Results from a clinical sample indicated that patients with OCD washing concerns scored significantly higher than patients with OCD without washing concerns on both Core Disgust and Contamination-Based Disgust, but not on Animal Reminder Disgust. These findings are discussed in the context of the refinement of the DS to promote a more psychometrically sound assessment of disgust sensitivity.


A p65/p95 neural surface receptor is expressed at the S-G2 phase of the cell cycle and defines distinct populations.
A surface receptor complex of Mr approximately 65 000 (p65) and approximately 95 000 (p95) is expressed in cells of the central nervous system of mice. This receptor is recognized by monoclonal antibody 87.92.6 or by reovirus type 3 haemagglutinin as unnatural ligands. The p65/p95 receptor is expressed mostly in neural embryonic precursors undergoing proliferation, especially those in the S-G2 phase of the cell cycle. Receptor expression decreases progressively throughout embryogenesis to low but detectable levels in the adult brain. Biochemical characterization revealed that the neural p65/p95 receptor complex is indistinguishable from the p65/p95 receptor expressed in T cells, where receptor ligation leads to a mitogenic block. In neural and lymphoid tissues the p65/p95 receptor (or an associated protein) possesses a tyrosine kinase enzymatic activity. Receptor ligation in neural cells resulted in the rapid tyrosine phosphorylation of cellular proteins which are different from substrates phosphorylated in T cells. Differential substrate coupling to the receptor may account for differences in signal transduction and biology between neural cells and T cells. Further study of this receptor complex may help define important features of neural proliferation, differentiation and survival.


Publicly funded medical savings accounts: expenditure and distributional impacts in Ontario, Canada.
This paper presents the findings from simulations of the introduction of publicly funded medical savings accounts (MSAs) in the province of Ontario, Canada. The analysis exploits a unique data set linking population-based health survey information with individual-level information on all physician services and hospital services utilization over a four-year period. The analysis provides greater detail along three dimensions than have previous analyses: (1) the distributional impacts of publicly funded MSAs across individuals of differing health statuses, incomes, ages, and current expenditures; (2) the impact of differing degrees of risk adjustment for MSA contributions; and (3) the impact of MSA funding over multiple years, incorporating year-to-year variation in spending at the individual level. In addition, it analyses more plausible designs for publicly funded MSAs than the existing studies. Government uses information available from year t - 1 to allocate its budget for year t in a manner that is ex ante fiscally neutral for the public sector: the government first withholds funds equal to expected catastrophic insurance payments under the MSA plan, and then allocates only the balance to individual MSA accounts. The government captures the savings associated with reduced health-care utilization under MSAs and we examine deductibles that vary by income rather than by current health-care expenditures. The impacts on public expenditures under these designs are more modest than in the previous studies and under plausible assumptions MSAs are predicted to decrease public expenditures. MSAs, however, are also predicted to have unavoidable negative distributional consequences with respect to both public expenditures and out-of-pocket spending.


The correlation between serum 25-hydroxy-vitamin D levels and anti-SARS-CoV-2 S-RBD IgG and neutralizing antibody levels among cancer patients receiving COVID-19 vaccines.
During the coronavirus disease 2019 (COVID-19) pandemic, vitamin D has been established as an immune-modulator that reduces pro-inflammatory damage which effectively diminish the severity of COVID-19. Vitamin D also has a significant effect against influenza and dengue and increase the seroconversion following influenza vaccination. To date, the role of vitamin D in optimizing the efficacy of COVID-19 vaccines remains unclear. This study aimed to analyze the correlation between serum 25-hydroxy-cholecalciferol or 25(OH)D levels and anti-SARS-CoV-2 S-RBD IgG and neutralizing antibody levels among cancer patients. A multicenter cross-sectional study was conducted among solid and hematologic cancer patients who were vaccinated with two doses of the same types of COVID-19 vaccines (either mRNA, non-replicating viral vector, or inactivated) within 6 months. The median serum 25(OH)D level in 119 cancer patients was 36.36 [IQR = 30.30] ng/mL. The seropositivity of S-RBD IgG and NAb reached 93.3 and 94.1%, respectively. The S-RBD IgG level was significantly higher in the sufficient group (median = 414.07 [1,441.83] AU/mL) than in the deficient group (median = 91.56 [652.00] AU/mL) (p-value = 0.049). Among non-chemotherapy subjects, the anti-SARS-CoV-2 S-RBD IgG levels had a significant positive correlation with 25(OH)D levels (p-value = 0.03; R = 0.588). The NAb levels also showed significantly positive correlation with 25(OH)D level (p-value = 0.005; R = 0.561). The 25(OH)D levels were positively correlated with S-RBD IgG levels among subjects younger than 60 years old (p-value = 0.047; R = 0.136). However, serum 25 (OH)D levels showed no such correlation with S-RBD IgG levels among subjects older than 60 years old (p-value = 0.933; R = 0.136). Both anti-SARS-CoV-2 S-RBD IgG and NAb levels developed moderate correlation with 25(OH)D levels among subjects treated without chemotherapy. The S-RBD IgG levels also had positive correlation with 25(OH)D levels among subjects younger than 60 years old. Thus, we recommended cancer patients to maintain serum 25(OH)D levels above 30 ng/mL (75 nmol/L) to enhance the efficacy of COVID-19 vaccines.


Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5β1 complex and triggering FAK-mediated Akt and TGFβ signaling pathways.
Head and neck squamous cell carcinoma (HNSCC) remains a formidable clinical challenge due to its high recurrence rate and limited targeted therapeutic options. This study aims to elucidate the role of tensin 4 (TNS4) in the pathogenesis of HNSCC across clinical, cellular, and animal levels. We found a significant upregulation of TNS4 expression in HNSCC tissues compared to normal controls. Elevated levels of TNS4 were associated with adverse clinical outcomes, including diminished overall survival. Functional assays revealed that TNS4 knockdown attenuated, and its overexpression augmented, the oncogenic capabilities of HNSCC cells both in vitro and in vivo. Mechanistic studies revealed that TNS4 overexpression promotes the interaction between integrin α5 and integrin β1, thereby activating focal adhesion kinase (FAK). This TNS4-mediated FAK activation simultaneously enhanced the PI3K/Akt signaling pathway and facilitated the interaction between TGFβRI and TGFβRII, leading to the activation of the TGFβ signaling pathway. Both of these activated pathways contributed to HNSCC tumorigenesis. Additionally, we found that hypoxia-inducible factor 1α (HIF-1α) transcriptionally regulated TNS4 expression. In conclusion, our findings provide the basis for innovative TNS4-targeted therapeutic strategies, which could potentially improve prognosis and survival rates for patients with HNSCC.


[Detection of HIV antibodies in pooled sera].
The use of sera mixtures for the detection of HIV antibodies was studied in a population of low prevalence (0.006%), using the diagnosis systems of national production: Recombinant HIV UMELISA and RECHIV 1 + 2. The systems were evaluated with individual samples and mixtures of 5 and 10 sera from healthy blood donors and from HIV-1 and/or HIV-2 positive and undetermined persons. It was observed that the utilization of mixtures of 10 sera is not feasible; however, the use of mixtures of 5 affects neither the specificity nor the sensitivity of the systems studied.


DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.
The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.