Smart polyaniline nanoparticles with thermal and photothermal sensitivity.
Conductive polyaniline nanoparticles (PANI NPs) are synthesized by oxidation of aniline with persulfate in acid media, in the presence of polymeric stabilizers: polyvinilpyrrolidone (PVP), poly(N-isopropylacrylamide) (PNIPAM), and hydroxylpropylcellulose (HPC). It is observed that the size of the nanoparticles obtained depends on the polymeric stabilizer used, suggesting a mechanism where the aggregation of polyaniline molecules is arrested by adsorption of the polymeric stabilizer. Indeed, polymerization in the presence of a mixture of two polymers having different stabilizing capacity (PVP and PNIPAM) allows tuning of the size of the nanoparticles. Stabilization with biocompatible PVP, HPC and PNIPAM allows use of the nanoparticle dispersions in biological applications. The nanoparticles stabilized by thermosensitive polymers (PNIPAM and HPC) aggregate when the temperature exceeds the phase transition (coil to globule) temperature of each stabilizer (Tpt = 32 °C for PNIPAM or Tpt = 42 °C for HPC). This result suggests that an extended coil form of the polymeric stabilizer is necessary to avoid aggregation. The dispersions are reversibly restored when the temperature is lowered below Tpt. In that way, the effect could be used to separate the nanoparticles from soluble contaminants. On the other hand, the PANI NPs stabilized with PVP are unaffected by the temperature change. UV-visible spectroscopy measurements show that the nanoparticle dispersion changes their spectra with the pH of the external solution, suggesting that small molecules can easily penetrate the stabilizer shell. Near infrared radiation is absorbed by PANI NPs causing an increase of their temperature which induces the collapse of the thermosensitive polymer shell and aggregation of the NPs. The effect reveals that it is possible to locally heat the nanoparticles, a phenomenon that can be used to destroy tumor cells in cancer therapy or to dissolve protein aggregates of neurodegenerative diseases (e.g. Alzheimer). Moreover, the long range control of aggregation can be used to modulate the nanoparticle residence inside biological tissues.


Molecular Dynamics Simulations of Deformation Mechanisms in the Mechanical Response of Nanoporous Gold.
The mechanical behaviour of nanoporous gold has so far been the subject of studies for bicontinuous morphologies, while the load transfer between ligaments is the primary challenge for using nanoporous structures-especially membranes with nanopores-in single-molecule sensors. This work studies the pore shape effect on deformation mechanisms of nanoporous gold membranes through molecular dynamics simulations. Tension and compression tests are carried out for nanoporous gold with circular, elliptical, square and hexagonal pore shapes. A significant pore shape effect on the mechanical properties is observed with distinct load transfer capabilities. A uniform stress transfer between ligaments constitutes a distinguished set of mechanical responses for structures with the hexagonal pore shape under tension, while a unique stress distribution in nanoporous with the circular pore shape introduces a high strength and ductile structure under compression. Further to shed light on the existing experimental observations, this work provides a comprehensive study on load transfer capabilities in the mechanical behaviour of nanoporous gold for sensing applications.


Radical-polar crossover reactions of vinylboron ate complexes.
Vinyl boronic esters are valuable substrates for Suzuki-Miyaura cross-coupling reactions. However, boron-substituted alkenes have drawn little attention as radical acceptors, and the radical chemistry of vinylboron ate complexes is underexplored. We show here that carbon radicals add efficiently to vinylboron ate complexes and that their adduct radical anions undergo radical-polar crossover: A 1,2-alkyl/aryl shift from boron to the α-carbon sp2 center provides secondary or tertiary alkyl boronic esters. In contrast to the Suzuki-Miyaura coupling, a transition metal is not required, and two carbon-carbon bonds are formed. The valuable boronic ester moiety remains in the product and can be used in follow-up chemistry, enlarging the chemical space of the method. The cascade uses commercial starting materials and provides access to perfluoroalkylated alcohols, γ-lactones, γ-hydroxy alkylnitriles, and compounds bearing quaternary carbon centers.


Suicides and suicide attempts in the U.S. Military, 2008-2010.
The Department of Defense Suicide Event Report Program collects extensive information on suicides and suicide attempts from the U.S. Air Force, Army, Marine Corps, and Navy. Data are compiled on demographics, suicide event details, behavioral health treatment history, military history, and information about other potential risk factors such as psychosocial stressors that were present at the time of the event. The ultimate goal of this standardized suicide surveillance program is to assist suicide prevention in the U.S. military. Descriptive data are presented on 816 suicides and 1,514 suicide attempts reported through the program between 2008 and 2010.


Milk and cheese fatty acid composition in sheep fed Mediterranean forages with reference to conjugated linoleic acid cis-9,trans-11.
Two experiments were undertaken to evaluate the effect on milk and cheese fatty acid composition of feeding different fresh forages to dairy sheep both in winter (experiment 1, growing stage of the forages, early lactating ewes) and in spring (experiment 2, reproduction stage of the forages, midlactating ewes). Four forage species were compared: annual ryegrass (RY, Lolium rigidum Gaudin), sulla (SU, Hedysarum coronarium L.), burr medic (BM, Medicago polymorpha L.), and a daisy forb (CH, Chrysanthemum coronarium L.). The forages were cut twice daily and offered ad libitum to 4 replicate groups of Sarda dairy sheep (groups RY, SU, BM, and CH). The CH forage was particularly rich in linoleic acid in both periods, whereas BM and SU forages were rich in linolenic acid in winter and spring, respectively. Milk fatty acid composition was affected by the forage in both experiments. Milk conjugated linoleic acid and vaccenic acid contents were higher in CH and BM groups (winter) and CH group (spring) than in the other groups. No differences were observed when comparing fatty acid profile between milk, 1-d-old cheeses, and 60-d-old cheeses within experimental groups, suggesting that the fatty acid recovery rates during cheese making and ripening were not affected by the feeding regimens. After stepwise discriminant analyses of the pooled data, the milks and cheeses sourced in the different feeding regimens differed among them. Based on these results, we conclude that it is possible to manipulate the fatty acid profile of sheep dairy produce to maximize the content of beneficial fatty acids by the use of appropriate fresh forage-based regimens.


Effect of music care on depression and behavioral problems in elderly people with dementia in Taiwan: a quasi-experimental, longitudinal study.
The purpose was to examine the effectiveness of music care on cognitive function, depression, and behavioral problems among elderly people with dementia in long-term care facilities in Taiwan. The study had a quasi-experimental, longitudinal research design and used two groups of subjects. Subjects were not randomly assigned to experimental group (n = 90) or comparison group (n = 56). Based on Bandura's social cognition theory, subjects in the experimental group received Kagayashiki music care (KMC) twice per week for 24 weeks. Subjects in the comparison group were provided with activities as usual. Results found, using the control score of the Clifton Assessment Procedures for the Elderly Behavior Rating Scale (baseline) and time of attending KMC activities as a covariate, the two groups of subjects had statistically significant differences in the mini-mental state examination (MMSE). Results also showed that, using the control score of the Cornell Scale for Depression in Dementia (baseline) and MMSE (baseline) as a covariate, the two groups of subjects had statistically significant differences in the Clifton Assessment Procedures for the Elderly Behavior Rating Scale. These findings provide information for staff caregivers in long-term care facilities to develop a non-invasive care model for elderly people with dementia to deal with depression, anxiety, and behavioral problems.


Carcinogenic and non-carcinogenic health risk of arsenic ingestion via drinking water in Langat River Basin, Malaysia.
The prolonged persistence of toxic arsenic (As) in environment is due to its non-biodegradable characteristic. Meanwhile, several studies have reported higher concentrations of As in Langat River. However, it is the first study in Langat River Basin, Malaysia, that As concentrations in drinking water supply chain were determined simultaneously to predict the health risks of As ingestion. Water samples collected in 2015 from the four stages of drinking water supply chain were analysed for As concentration by inductively coupled plasma mass spectrometry. Determined As concentrations along with the time series data (2004-2015) were significantly within the maximum limit 0.01 mg/L of drinking water quality standard set by World Health Organization. The predicted As concentration by auto-regression moving average was 3.45E-03 mg/L in 2020 at 95% level based on time series data including climatic control variables. Long-term As ingestion via household filtration water at Langat Basin showed no potential lifetime cancer risk (LCR) 9.7E-06 (t = 6.68; p = 3.37E-08) as well as non-carcinogenic hazard quotient (HQ) 4.8E-02 (t = 6.68; p = 3.37E-08) risk at 95% level. However, the changing landscape, ex-mining ponds and extensive use of pesticides for palm oil plantation at Langat Basin are considered as the major sources of increased As concentration in Langat River. Therefore, a two-layer water filtration system at Langat Basin should be introduced to accelerate the achievement of sustainable development goal of getting safe drinking water supply.


[Plan for Improving the Initial Ambulation of Acute Stroke Patients].
Acute stroke patients should receive a rehabilitation assessment within 24-48 hours of hospitalization. Initial ambulation is known to reduce the occurrence of complications, improve the ability to perform activities of daily living, and reduce the risk of long-term disability. To raise the initial ambulation willingness of acute stroke patients and to increase the willingness of these patients to receive rehabilitation treatment as soon as possible in order to reduce the long-term physical damage of the stroke incident. To develop and implement standard operating procedures for the initiation of ambulation (first time leaving the hospital bed) in acute stroke patients, to use health education brochures with texts and illustrations, and to have nurses physically assist patients to initiate ambulation. The rate of ambulation initiation in acute stroke patients rose from 32.0% pre-intervention to 85.4% post-intervention. Acute stroke patients who initiate ambulation soon after experiencing a stroke may reduce their risk of acute complications, increase their ability to perform activities of daily living, and reduce the risk of long-term disability. Thus, encouraging early ambulation is extremely important to improving the prognosis of this patient population.


Direct four-dimensional structural and functional imaging of cardiovascular dynamics in mouse embryos with 1.5 MHz optical coherence tomography.
High-resolution three-dimensional (3D) imaging of cardiovascular dynamics in mouse embryos is greatly desired to study mammalian congenital cardiac defects. Here, we demonstrate direct four-dimensional (4D) imaging of the cardiovascular structure and function in live mouse embryos at a ∼43 Hz volume rate using an optical coherence tomography (OCT) system with a ∼1.5 MHz Fourier domain mode-locking swept laser source. Combining ultrafast OCT imaging with live mouse embryo culture protocols, 3D volumes of the embryo are directly and continuously acquired over time for a cardiodynamics analysis without the application of any synchronization algorithms. We present the time-resolved measurements of the heart wall motion based on the 4D structural data, report 4D speckle variance and Doppler imaging of the vascular system, and quantify spatially resolved blood flow velocity over time. These results indicate that the ultra-high-speed 4D imaging approach could be a useful tool for efficient cardiovascular phenotyping of mouse embryos.


Integration of taxa abundance and occurrence frequency to identify key gut bacteria correlated to clinics in Crohn's disease.
Bacteria abundance alternation in the feces or mucosa of Crohn's disease (CD) patients has long been applied to identify potential biomarkers for this disease, while the taxa occurrence frequency and their correlations with clinical traits were understudied. A total of 97 samples from the feces and gut mucosa were collected from CD patients and healthy controls (HCs), 16S rRNA-based analyses were performed to determine the changes in taxa abundance and occurrence frequency along CD and to correlate them with clinical traits. The results showed that bacteria communities were divergent between feces and mucosa, while the taxa abundance and occurrence frequency in both partitions showed similar exponential correlations. The decrease of specific fecal bacteria was much more effective in classifying the CD and HCs than that of the mucosal bacteria. Among them, Christensenellaceae_R-7_group and Ruminococcus were predicted as biomarkers by using random forest algorithm, which were persistently presented (> 71.40% in frequency) in the feces of the HCs with high abundance, whereas transiently presented in the feces (< 5.5% in frequency) and mucosa (< 18.18% in frequency) of CD patients with low abundance. Co-occurrence network analysis then identified them as hub taxa that drive the alternations of other bacteria and were positively correlated to the circuiting monocytes. The loss of specific bacteria in the healthy gut may cause great disturbance of gut microbiota, causing gut bacteria dysbiosis and correlated to immune disorders along CD, which might not only be developed as effective noninvasive biomarkers but also as therapy targets.


Feshbach resonance in optical lattices and the quantum Ising model.
Motivated by experiments on heteronuclear Feshbach resonances in Bose mixtures, we investigate s-wave pairing of two species of bosons in an optical lattice. The zero temperature phase diagram supports a rich array of superfluid and Mott phases and a network of quantum critical points. This topology reveals an underlying structure that is succinctly captured by a two-component Landau theory. Within the second Mott lobe we establish a quantum phase transition described by the paradigmatic longitudinal and transverse field Ising model. This is confirmed by exact diagonalization of the 1D bosonic Hamiltonian. We also find this transition in the homonuclear case.


FORMULATION AND TECHNOLOGY DEVELOPMENT OF HERBAL PHENOLIC BIOPOLYMER-CONTAINING FILMS FOR BURN TREATMENT.
Application of phytofilms based on biosolublepolymers is considered as a prospectivemethod for burn treatment . Herbal remedies contain biologically active substances, that are relatively less toxic, do not cause skin irritation or allergic reactions and, importantly, affectstrains of the microorganisms and viruses resistant to antibiotics and synthetic drugs. Nowadays, the advantages are given to such burn healing drugs, which along with high specific efficacy, have analgesic, anti-inflammatory and antimicrobial effects, and don't irritate the tissues. The mentioned peculiarities are characteristic for a new herbal phenolic biopolymer poly[3-(3,4-dihydroxyphenyl) glyceric acid](PDGA), isolated from the roots and stems of different comfrey species . The aim of the study was the development of the formulation and technology of biosoluble films for burn treatment on the basis of PDGA. The optimal content of phytofilm for burn healing was selected on the basis of the biopharmaceutical study results. The impact of the film-former on the quality, adhesion and moisture absorption of the phytofilmhas been studied. The optimal degree of the phytofilm moisture, determining its high adhesive properties,was established. The film prepared on the basis of sodium alginate, with 30.4% humidity, demonstrated the greatest adhesion strength. After investigation of the PDGA release it was found, that the hydrophilic bases such as: sodium carboxymethyl-cellulose (69.2%) andsodium alginate (78,65%) appeared to be optimal among the others. At the same time, taking into consideration the disadvantages of sodium carboxymethyl-cellulose (tautening effect on burnt surface, relatively low stability), a film based on sodium alginate has been chosen. The manufacturing technology for obtaining PDGA-containing phytofilm by casting is proposed. Theshelf-lifeofproposedPDGA-containingphytofilmis 2 years.


BRAFV600 mutations in solid tumors, other than metastatic melanoma and papillary thyroid cancer, or multiple myeloma: a screening study.
Mutations in the BRAF gene have been implicated in several human cancers. The objective of this screening study was to identify patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma harboring activating BRAFV600 mutations for enrollment in a vemurafenib clinical study. Formalin-fixed, paraffin-embedded tumor samples were collected and sent to a central laboratory to identify activating BRAFV600 mutations by bidirectional direct Sanger sequencing. Overall incidence of BRAFV600E mutation in evaluable patients (n=548) was 3% (95% confidence interval [CI], 1.7-4.7): 11% in colorectal tumors (n=75), 6% in biliary tract tumors (n=16), 3% in non-small cell lung cancers (n=71), 2% in other types of solid tumors (n=180), and 3% in multiple myeloma (n=31). There were no BRAFV600 mutations in this cohort of patients with ovarian tumors (n=68), breast cancer (n=86), or prostate cancer (n=21). This multicenter, national screening study confirms previously reported incidences of BRAFV600 mutations from single-center studies. Patients identified with BRAFV600 mutations were potentially eligible for enrollment in the VE-BASKET study.


Validation of Varian TrueBeam electron phase-spaces for Monte Carlo simulation of MLC-shaped fields.
This work evaluates Varian's electron phase-space sources for Monte Carlo simulation of the TrueBeam for modulated electron radiation therapy (MERT) and combined, modulated photon and electron radiation therapy (MPERT) where fields are shaped by the photon multileaf collimator (MLC) and delivered at 70 cm SSD. Monte Carlo simulations performed with EGSnrc-based BEAMnrc/DOSXYZnrc and penelope-based PRIMO are compared against diode measurements for 5 × 5, 10 × 10, and 20 × 20 cm(2) MLC-shaped fields delivered with 6, 12, and 20 MeV electrons at 70 cm SSD (jaws set to 40 × 40 cm(2)). Depth dose curves and profiles are examined. In addition, EGSnrc-based simulations of relative output as a function of MLC-field size and jaw-position are compared against ion chamber measurements for MLC-shaped fields between 3 × 3 and 25 × 25 cm(2) and jaw positions that range from the MLC-field size to 40 × 40 cm(2). Percent depth dose curves generated by BEAMnrc/DOSXYZnrc and PRIMO agree with measurement within 2%, 2 mm except for PRIMO's 12 MeV, 20 × 20 cm(2) field where 90% of dose points agree within 2%, 2 mm. Without the distance to agreement, differences between measurement and simulation are as large as 7.3%. Characterization of simulated dose parameters such as FWHM, penumbra width and depths of 90%, 80%, 50%, and 20% dose agree within 2 mm of measurement for all fields except for the FWHM of the 6 MeV, 20 × 20 cm(2) field which falls within 2 mm distance to agreement. Differences between simulation and measurement exist in the profile shoulders and penumbra tails, in particular for 10 × 10 and 20 × 20 cm(2) fields of 20 MeV electrons, where both sets of simulated data fall short of measurement by as much as 3.5%. BEAMnrc/DOSXYZnrc simulated outputs agree with measurement within 2.3% except for 6 MeV MLC-shaped fields. Discrepancies here are as great as 5.5%. TrueBeam electron phase-spaces available from Varian have been implemented in two distinct Monte Carlo simulation packages to produce dose distributions and outputs that largely reflect measurement. Differences exist in the profile shoulders and penumbra tails for the 20 MeV phase-space off-axis and in the outputs for the 6 MeV phase-space.


Exploring Generational Differences of British Ethnic Minorities in Smoking Behavior, Frequency of Alcohol Consumption, and Dietary Style.
Background: This article explores ethnic minority generational differences in smoking behavior, frequency of alcohol consumption, and dietary style in Britain, and whether these differences can be explained by generational differences in socioeconomic status and ethnic identity. Method: Multivariate analyses using wave 2 (2010-2012) and wave 5 (2013-2015) of the United Kingdom Household Longitudinal Study on smoking behavior, frequency of alcohol consumption, and dietary style from 59,189 White British, 1690 Indians, 960 Pakistanis, 555 Bangladeshis, 1060 Black Caribbeans, and 1059 Black Africans, adjusted for demographic characteristics, socioeconomic status and ethnic identity. Results: While we find little evidence for generational differences in dietary style, second-generation Indians, Pakistanis, and Black Caribbeans have a significantly higher probability of smoking than the first-generation, and all second-generation minorities are significantly more likely to consume alcohol than their first-generation counterparts. Such generational differences in alcohol consumption are partly explained by second-generation minorities' weakened ethnic identity and higher socioeconomic status. Conclusions: This study facilitates a better understanding of minority generational differences in health behaviors and the role of socioeconomic status and ethnic identity, highlighting the need for future policy interventions to target certain second-generation ethnic minorities who have adopted certain host society unhealthy lifestyles.


Sporotrichosis: an unusual disseminated cutaneous case and a fatal pulmonary case.
Two unusual cases of sporotrichosis are presented. One patient had disseminated vesicular skin lesions which yielded Sporothrix schenckii on culture. The other, with extensive pulmonary sporotrichosis, continued to have sputum cultures positive for S schenckii during three years of intensive chemotherapy.


Sodium stibogluconate (Pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid beta-oxidation in Leishmania mexicana amastigotes.
The biochemical mechanism of action of antimony (Sb) in pentavalent form complexed to gluconic acid (sodium stibogluconate)--the drug of choice for the leishmaniases--has been only slightly investigated. We recently reported that, in stibogluconate-exposed Leishmania mexicana amastigotes, there is a dose-dependent decrease in the ATP/ADP ratio [Berman et al., Antimicrob. Agents Chemother. 27, 916 (1985)]. To investigate mechanisms by which ADP phosphorylation to ATP might be inhibited, stibogluconate-exposed amastigotes were incubated with [14C]glucose, fatty acid, or acetate, and 14CO2 production was determined. In organisms exposed to 500 micrograms Sb/ml, formation of 14CO2 from [6-14C]glucose and [1-14C]palmitate was inhibited 69 and 67% respectively. In comparison, formation of 14CO2 from [1-14C]glucose and [2-14C]acetate was inhibited less than 15%. These results suggest that glucose catabolism via glycolytic enzymes and fatty acid beta-oxidation, but not glucose metabolism via the hexosemonophosphate shunt or the citric acid cycle, is specifically inhibited in stibogluconate-exposed Leishmania mexicana amastigotes. Inhibition of these pathways suggests a mechanism for the inhibition of ADP phosphorylation previously reported.


[Filling the 3D scaffolds by the stromal bone marrow cells depends on the methods of cell seeding and the scaffold surface modifications].
The distribution of bone marrow stromal cells (BMSC) is studied in a 3D poly(L,L-lactide) scaffolds. It is shown that the population of cells seeding into the scaffold with a peristaltic pump (dynamic method) allows the penetration of cells inside of the scaffold compared with the application of the cell suspension on the scaffold surface (static method). In contrast to cells seeding to scaffold by dynamic method the cells seeding by static method migrate from scaffolds in the first few days almost completely. It is found that BMSCs cultured in 3D polylactide scaffold modified by fibrin form colonies, while BMSCs cultured in 3D polylactide-scaffold modified by collagen type I distribute inside scaffold such single cells.


Genetic determinants of aggressive breast cancer.
The development and spread of breast and other human cancers are caused by the overexpression, mutation, and/or deletion of specific genes that drive these events. Finding genetic and molecular differences between cancerous and healthy cells can reveal the genetic determinants of cancer. This knowledge results in a better understanding of the carcinogenic process and improved predictive power, with implications for identifying new drug targets, designing novel therapies, and improving preclinical and clinical studies. We review the concepts of biomarker, genetic marker, and genetic determinant in cancer, with particular focus on the most aggressive and lethal form of breast cancer, termed inflammatory breast cancer (IBC). Using IBC as an example, we describe in detail the approaches to identify the genes that are responsible for-and not merely associated with-this disease.


The role of the histone H3 variant CENPA in prostate cancer.
Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth.


Advances in dyslipidemia management for prevention of atherosclerosis: PCSK9 monoclonal antibody therapy and beyond.
In 2003, select families with familial hypercholesterolemia were first identified to have gain-of-function mutations for proprotein convertase subtilisin kexin type 9 (PCSK9) followed, in 2006, by the identification of those with lifelong low levels of LDL-C and lowered atherosclerotic cardiovascular disease (ASCVD) risk who had loss-of-function PCSK9 mutations. These discoveries led to the rapid development of PSCK9-targeted monoclonal antibody (PCSK9 mAb) therapies and, in 2015, 2 'fully-humanized' PCSK9 mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries. In a wide range of high risk patients, with and without ASCVD, these PCSK9 mAbs, as once or twice monthly subcutaneous injections, potently reduce LDL-C 50-65% beyond levels achieved by maximally tolerated statin therapy; approximately one-third of patients achieve LDL-C levels <25 mg/dL. In the US, PCSK9 mAb therapy has current limited indications for persons with ASCVD or familial hypercholesterolemia requiring additional LDL-C reduction beyond maximally tolerated statin therapy. The first of the ASCVD outcomes-driven trials, the FOURIER trial has very recently shown in over 27,000 subjects randomized to evolocumab or placebo on top of moderate or high intensity statin therapy, a 15% risk reduction in the primary and 20% reduction in the secondary outcome over 2.2 years of treatment. Also of interest in patients with coronary artery disease on statin therapies, once-monthly evolocumab treatment, for only 76 weeks, resulted in significant plaque atheroma volume regression, as assessed by serial intravascular ultrasonography imaging, in approximately two-thirds of treated patients. Finally, in development is a highly durable RNA interference therapeutic inhibitor of PCSK9 synthesis which from a single dosage has been shown to maintain, for 6 months, a 75% reduction in PCSK9 levels and 50% reductions in LDL-C levels. The potential role of this vaccination-like product, as well as currently available PCSK9 mAb therapies, represents significant therapeutic advances to address ASCVD residual risk.


[Evolution of pre and postoperative renographic parameters in pyeloreteral juntion obstruction syndrome].
With the objective of observing the modifications that the postoperative Diuretic Renography (DR) curve shows and determining how the quantitative parameters of this exploration (Differential Renal Function (DRF), Peak Time (PT), Half Time (HT), descent of maximum activity at 10 min (DMA10)) can be modified, the records of 50 patients affected by unilateral pyeloureteral junction obstruction and without any other associated pathology treated between 1991 and 2001, were revised. The age of the patients was between 1 month and 12 years (average 2 years 7 months). Of the 50 patients, 31 were male and in 28 of the cases were affected on the left side. Patient selection was random. The preoperative evaluation was made using ultrasound (US), intravenous urography (IU), voiding cystourethrography (VCU), and RD. The RD technique and surgical intervention were standardized and the latter were performed by the same surgeon. Postoperative control was made with US and/or IU and RD between 6 and 18 months following surgery, even though total follow up ranged from 6 months to 10 years (average 38.24 months). In all of the cases the follow up US and/or IU results were satisfactory, even though there was residual pyelic ectasia and absence of tension. The morphology of the preoperative curves was mostly obstructive or partially obstructive without lasix response, the curves became normal in 9 cases and partially obstructive with a good response to lasix in 38. The 3 remaining cases that corresponded to the hypofunctional kidney curve did not change. The DRF did not present major variations. The postoperative PT decreased in 62% of the cases. The HT and DMA10 improved in very few cases. In conclusion, it can be said that in spite of a good surgical outcome, the patterns of the postoperative renographic curve often do not completely normalize, major variations in the postoperative DRF are not expected, and with a diminshed postoperative PT a favorable pyeloplasty outcome can be appreciated. HT and DMA10 indicate improvement when they decrease, but do not indicate that the disease has reappeared when they do not change or increase.


Microfluidic devices fabricated using fast wafer-scale LED-lithography patterning.
Current lithography approaches underpinning the fabrication of microfluidic devices rely on UV exposure of photoresists to define microstructures in these materials. Conventionally, this objective is achieved with gas discharge mercury lamps, which are capable of producing high intensity UV radiation. However, these sources are costly, have a comparatively short lifetime, necessitate regular calibration, and require significant time to warm up prior to exposure taking place. To address these limitations we exploit advances in solid state sources in the UV range and describe a fast and robust wafer-scale laboratory exposure system relying entirely on UV-Light emitting diode (UV-LED) illumination. As an illustration of the potential of this system for fast and low-cost microfluidic device production, we demonstrate the microfabrication of a 3D spray-drying microfluidic device and a 3D double junction microdroplet maker device.


Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages: role of liver X receptor α.
The transient receptor potential vanilloid type 1 (TRPV1) is crucial in the pathogenesis of atherosclerosis; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear. Here, we show increased TRPV1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein E-deficient mice. Exposure of mouse bone-marrow-derived macrophages to oxidized low-density lipoprotein (oxLDL) upregulated the expression of TRPV1. In addition, oxLDL activated TRPV1 and elicited calcium (Ca(2+)) influx, which were abrogated by the pharmacological TRPV1 antagonist capsazepine. Furthermore, oxLDL-induced lipid accumulation in macrophages was ameliorated by TRPV1 agonists but exacerbated by TRPV1 antagonist. Treatment with TRPV1 agonists did not affect the internalization of oxLDL but promoted cholesterol efflux by upregulating the efflux ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Moreover, the upregulation of ABC transporters was mainly through liver X receptor α-(LXRα-) dependent regulation of transcription. Moreover, the TNF-α-induced inflammatory response was alleviated by TRPV1 agonists but aggravated by the TRPV1 antagonist and LXR α siRNA in macrophages. Our data suggest that LXR α plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages.


Early origin of sweet perception in the songbird radiation.
Early events in the evolutionary history of a clade can shape the sensory systems of descendant lineages. Although the avian ancestor may not have had a sweet receptor, the widespread incidence of nectar-feeding birds suggests multiple acquisitions of sugar detection. In this study, we identify a single early sensory shift of the umami receptor (the T1R1-T1R3 heterodimer) that conferred sweet-sensing abilities in songbirds, a large evolutionary radiation containing nearly half of all living birds. We demonstrate sugar responses across species with diverse diets, uncover critical sites underlying carbohydrate detection, and identify the molecular basis of sensory convergence between songbirds and nectar-specialist hummingbirds. This early shift shaped the sensory biology of an entire radiation, emphasizing the role of contingency and providing an example of the genetic basis of convergence in avian evolution.


Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population.
Autism is a childhood neuro-developmental disorder, and Reelin (RELN) is an important candidate gene for influencing autism. This study aimed at investigating the influence of genetic variants of the RELN gene on autism susceptibility. In this study, 205 autism patients and 210 healthy controls were recruited and the genetic variants of the RELN gene were genotyped by the created restriction site-polymerase chain reaction (CRS-PCR) method. The influence of genetic variants on autism susceptibility was analyzed by association analysis, and the g.296596G > A genetic variant in exon10 of the RELN gene was detected. The frequencies of allele/genotype in autistic patients were significantly different from those in healthy controls, and a statistically significant association was detected between this genetic variant and autism susceptibility. Our data lead to the inference that the g.296596G > A genetic variant in the RELN gene has a potential influence on autism susceptibility in the Chinese Han population.


Ongoing efforts to improve the international nuclear and radiological emergency response.
It is recognised that states, through the development of a consistent, coherent and sustainable joint programme for improved and more efficient international responses to nuclear and radiological emergencies, could achieve a better and more cost-effective response capability. Enhanced efforts by IAEA member states and the IAEA secretariat to improve the implementation of the Convention on Early Notification of a Nuclear Accident and the Convention on Assistance in Case of a Nuclear Accident or Radiological Emergency have been initiated, establishing a national competent authority coordination group (NCACG) and a long-term action plan for the work.


Livestock-associated risk factors for pneumonia in an area of intensive animal farming in the Netherlands.
Previous research conducted in 2009 found a significant positive association between pneumonia in humans and living close to goat and poultry farms. However, as this result might have been affected by a large goat-related Q fever epidemic, the aim of the current study was to re-evaluate this association, now that the Q-fever epidemic had ended. In 2014/15, 2,494 adults (aged 20-72 years) living in a livestock-dense area in the Netherlands participated in a medical examination and completed a questionnaire on respiratory health, lifestyle and other items. We retrieved additional information for 2,426/2,494 (97%) participants from electronic medical records (EMR) from general practitioners. The outcome was self-reported, physician-diagnosed pneumonia or pneumonia recorded in the EMR in the previous three years. Livestock license data was used to determine exposure to livestock. We quantified associations between livestock exposures and pneumonia using odds ratios adjusted for participant characteristics and comorbidities (aOR). The three-year cumulative frequency of pneumonia was 186/2,426 (7.7%). Residents within 2,000m of a farm with at least 50 goats had an increased risk of pneumonia, which increased the closer they lived to the farm (2,000m aOR 1.9, 95% CI 1.4-2.6; 500m aOR 4.4, 95% CI 2.0-9.8). We found no significant associations between exposure to other farm animals and pneumonia. However, when conducting sensitivity analyses using pneumonia outcome based on EMR only, we found a weak but statistically significant association with presence of a poultry farm within 1,000m (aOR: 1.7, 95% CI 1.1-2.7). Living close to goat and poultry farms still constitute risk factors for pneumonia. Individuals with pneumonia were not more often seropositive for Coxiella burnetii, indicating that results are not explained by Q fever. We strongly recommend identification of pneumonia causes by the use of molecular diagnostics and investigating the role of non-infectious agents such as particulate matter or endotoxins.


Human plasma-derived material with clonidine displacing substance (CDS)-like properties contracts the isolated rat aorta.
1. The biological activity of a plasma-derived, clonidine displacing substance (CDS)-like material was tested on isolated rat aortic rings and compared to that of clonidine, an imidazoline with alpha 2-adrenoceptor agonist properties. 2. The CDS-like material was partially purified from expired human blood. This product inhibited in a dose-dependent manner the binding of [3H]-clonidine to rat brain membranes with a ki of 0.87 +/- 0.4 u ml-1, without affecting the binding of the alpha 1-antagonist, [3H]-WB4101. 3. When the CDS-like material (0.14-6 u ml-1) was applied to the bathing medium of isolated rat aortic rings, it caused dose-dependent contractions with an EC50 of 1.0 +/- 0.18 u ml-1. Clonidine also dose-dependently contracted rat aortic rings (EC50, 1.1 +/- 0.24 x 10(-7) M). The maximal tension developed in response to clonidine, however, was higher (1.37 +/- 0.15 g) compared to that developed in response to the CDS-like material (0.92 +/- 0.12 g). 4. Contractions induced by both CDS-like material and clonidine were antagonized by 5 x 10(-7) M rauwolscine, an alpha 2-adrenoceptor antagonist. Prazosin, an alpha 1-adrenoceptor antagonist, at 10(-8) M, greatly reduced contractions caused by clonidine while leaving those caused by CDS-like material unaffected. 5. The CDS-like material failed to alter the tension of intact or endothelium-denuded rat aortic rings which had been precontracted with methoxamine. Clonidine on the other hand, caused dose-dependent relaxations in intact, though not in denuded, precontracted rat aortic rings.(ABSTRACT TRUNCATED AT 250 WORDS)


[Distribution of donor-specific aKIR after unrelated allogeneic hematopoietic stem cell transplantation].
Objective: To analyze the distribution and proportion of donor-specific activated killer cell immunoglobulin like receptor (aKIR) genes and their clinical application values in unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Retrospective analyses of KIR genotyping using polymerase chain reaction with sequence specific primers (PCR-SSP) were performed in 216 pairs of donors and recipients. Results: The frequency of donor-specific KIR genes was 53.7% (116/216) in 216 patients receiving unrelated allo-HSCT, with the frequency of 78.3% (112/143) in the KIR genes mismatched group and 5.5% (4/73) in matched group. Of the 116 patients with detectable donor-specific KIR genes, 99.1% (115/116) patients had various donor-specific aKIR genes. Among 55 pairs of donors' KIR-Bx genotype and patients' KIR-AA genotype group, the most commonly observed genotypes were Bx1, Bx2, Bx3, Bx4, in which the donor-specific KIR genes were respectively KIR 3DS1, 2DL5A, 2DS5, 2DS1; KIR 3DS1, 2DL5A, 2DS3, 2DS1; KIR 2DS2, 2DL2; KIR 2DS2, 2DL2, 3DS1, 2DL5A, 2DS5, 2DS1. Of 44 pairs of donors' KIR-AA genotype and patients' KIR-Bx (AB) genotype group, 36.4% (16/44) recipients had donor-specific KIR2DS4 (FUL) gene. In 143 pairs of KIR mismatched group, the frequencies of donor-specific KIR genes were KIR2DS1 (35.7%) , KIR3DS1 (32.9%) , KIR2DS5 (29.4%) , KIR2DS4 (FUL) (25.9%) , KIR2DL2 (25.2%) , KIR2DS2 (24.5%) , KIR2DS3 (21.7%) and KIR3DL1 (8.4%) , respectively. Conclusion: The donor-specific aKIR genes mainly existed in KIR mismatched group after unrelated allo-HSCT, and the different pairs of donors' and patients' KIR genotypes led to the diverse donor-specific aKIR. But there were higher specific aKIR genes in higher frequency of KIR AA, Bx1, Bx2, Bx3, Bx4 genotypes. All these can provide the experimental basis for studying the role of the donor-specific aKIR genes on the prognosis of HSCT.


Trypanothione Reductase: A Target for the Development of Anti- Trypanosoma cruzi Drugs.
Chagas disease or American trypanosomiasis is a major parasitic disease in Latin America with restricted available treatment: nifurtimox and benznidazole. These two drugs are ineffective in the chronic phase of the disease; therefore, there is a need for the development of new, efficient and safe drugs for the treatment of this pathology. With this goal, one of the promising targets is trypanothione reductase (TR), a key enzyme in the metabolism of Trypanosoma cruzi. In this review, we analyse the importance of TR as a drug target, as well as the well-known and new inhibitors reported in the last decade as potential therapeutic agents for Chagas disease.


Supramolecular Host-Selective Activation of Iodoarenes by Encapsulated Organometallics.
Supramolecular hosts offer defined microenvironments that facilitate selective host-guest interactions, enabling reactivity that would otherwise be challenging in bulk solution. While impressive rate enhancements and selectivities have been reported, similar reactivity can often be accessed through modifications of reaction conditions even in the absence of the host. We report here an oxidative addition of aryl halides across the metal centers in Cu(I) and Pd(II) organometallics that is assisted by the presence of a supramolecular host, realized via electrostatic stabilization and increased local substrate concentrations. When reaction conditions were screened to assess background reactivity, alternative reactivity (typically decomposition) resulted, indicating that encapsulation led to host-selective reaction trajectories.


Prediction of survival in extrahepatic biliary atresia by hepatic duplex sonography.
The clinical course of biliary atresia patients is extremely variable. To optimize conservative treatment and correctly schedule liver transplantation, noninvasive investigations that are predictive of individual survival and that can be performed regularly are needed. In this study, the prognostic value of Doppler sonography was investigated in these patients. Thirty biliary atresia patients (age range, 1 month to 15.2 years; mean, 4.0 years) and 38 control subjects underwent standardized Doppler sonography of liver and spleen. Biochemical tests of liver function and of fibrogenesis were performed in parallel. Individual clinical outcome was registered 1 and 2 years later. In control subjects, maximum portal flow velocity (Vmax) was more than 16 cm/sec, and the hepatic vein flow pattern was triphasic. Among children with biliary atresia, those with diminished portal Vmax, a flattened hepatic vein flow curve, or a hepatic artery resistance index of 0.8 or more had significantly lower indices of hepatic protein synthesis (albumin, cholinesterase), higher bilirubin levels, and higher concentrations of markers of connective tissue turnover (procollagen peptides, laminin P1) than did those with normal Doppler sonography measurements. The rate of survival without transplantation during the following 2 years was significantly lower in children with abnormal Doppler findings. From portal and hepatic vein flow measurements, patient survival 2 years later could be predicted with an accuracy of 93%. In children with extrahepatic biliary atresia, Doppler sonography of the hepatic blood flow is a noninvasive indicator of disease severity. Moreover, it allows a highly accurate prediction of patient survival for the following 2 years.


PharMillenium '99--the second world pharmaceutical congress and exhibition. Accelerating the pipeline: from drug discovery to market. 1-3 February 1999, Washington DC, USA.
This highly interactive meeting effectively covered critical issues on every transaction from drug discovery through to development and commercialization. The program included company-specific descriptions of new discovery products, together with seminars by clinical research and site management organizations on the acceleration of development, pharmaco-economics, branding of products, direct-to-consumer advertising, global marketing, management, information technology and business strategy. There were approximately 50 sessions covered by 70 speakers.


Radical cascades using enantioenriched 7-azabenzonorbornenes and their applications in synthesis.
Tandem deoxygenation-neophyl-type radical rearrangement-electrophile trapping using xanthates from 7-azabenzonorbornadienes gives 3-exo-substituted 2-aza-5,6-benzonorbornenes, which in some cases undergo isomerisation to (aminomethyl)indenes. The starting xanthates are accessible in good yields and high enantiomeric ratios via asymmetric hydroboration of (aryne/pyrrole-derived) 7-azabenzonorbornadienes. Oxidation (using RuO(4)) and Birch reduction of the 2-aza-5,6-benzonorbornenes provide access to substituted pyrrolidines and tetrahydroindenes, respectively.


[Computer aided design and manufacture of individual laminate veneer].
In view of the instance of a damaged medial incisor, we have introduced a method using computer aided technology to design and manufacture the laminate veneer. Firstly, the data on preparation teeth was retrieved by the 3D-optical measuring system. Secondly, the triangle mesh model of preparation teeth was reconstructed by using the reversion project software. And the 3D model of the laminate veneer was constructed through some operations, such as extracting the edge line of preparation teeth, mirroring the integrity incisor and local freeform transform. The result has proved that the fabrication process is reliable and efficient. The dental restoration quality is steady and precise. The artifical laminate veneer has met the request of esthetical symmetry.


Modulation of ligand-gated ion channels by antidepressants and antipsychotics.
It is generally accepted that antidepressants and antipsychotics mediate their therapeutic effects via specific interaction with processes related to synaptic neurotransmission in the central nervous system. Besides their well-known classical mechanisms of action, antidepressants and antipsychotics show widely unknown effects, which might also contribute to the pharmacological profile of these agents. There is growing evidence that an interaction of these drugs with allosteric modulatory sites of ligand-gated ion channels (LGICs) might represent a yet unknown principle of action. Such interactions of psychopharmacological drugs with LGICs might play an important role both for the therapeutic efficacy and the side effect profile of these agents. In this review, we focus on the direct interaction of antidepressants and antipsychotics with LGICs, which may provide a basis for the development of novel psychopharmacological drugs.


The Role of lncRNAs TAPIR-1 and -2 as Diagnostic Markers and Potential Therapeutic Targets in Prostate Cancer.
In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.


Mechanisms of Action of a Herbal Formula Huangqi Guizhi Wuwu Tang for the Management of Post-Stroke Related Numbness and Weakness: A Computational Molecular Docking Study.
Stroke-related numbness and weakness (SRNW) are resultant symptoms of post-stroke sufferers. Existing research has supported the use of Huangqi Guizhi Wuwu Tang (HGWT) particularly for SRNW; however, their mechanisms of action have not been fully elucidated. Therefore, this study aimed to investigate the mechanisms of action of HGWT components targeting SRNW-related proteins through a computational molecular docking approach. Target proteins associated with SRNW were identified through DrugBank database and Open Targets database. Chemical compounds from each herb of HGWT were identified from the Traditional Chinese Medicine Systems Pharmacology and Analysis Platform (TCMSP). Autodock Vina was utilized and the cut-off criterion applied for protein-ligand complexes was a binding affinity score of ≤ -9.5 kcal/mol; selected protein-ligand complexes were identified using 3D and 2D structural analyses. The protein targets PDE5A and ESR1 have highlighted interactions with compounds (BS040, DZ006, DZ058, DZ118, and HQ066) which are the key molecules in the management of SRNW. PDE5A have bioactivity with the amino acid residues (Val230, Asn252, Gln133 and Thr166) throughout PDE5A-cGMP-PKG pathways which involved reduction in myofilament responsiveness. ESR1 were predicted to be critical active with site residue (Leu346, Glu419 and Leu387) and its proteoglycans pathway involving CD44v3/CD44 that activates rho-associated protein kinase 1 (ROCK1) and ankyrin increasing vascular smooth muscle. In conclusion, HGWT may provide therapeutic benefits through strong interactions between herbal compounds and target proteins of PDE5A and ESR1. Further experimental studies are needed to unequivocally support this result which can be valuable to increase the quality of life of post-stroke patients. Keywords Herbal medicine, Complementary and alternative medicine, Natural product, Post-stroke, Computational analysis.


Plasma von Willebrand factor level as a prognostic indicator of patients with metastatic colorectal carcinoma.
To evaluate the correlations of plasma von Willebrand factor (vWF) level with the distant metastasis and prognosis of patients with colorectal cancer. A total of 86 patients with histologically confirmed metastatic colorectal cancers receiving treatment at Taipei Veterans General Hospital were enrolled. All patients had measurable metastatic lesions and life expectancies of more than 3 mo. Plasma vWF levels were measured by immuno-turbidimetric assay and compared with results from 40 non-metastatic colorectal cancer patients and 22 healthy controls. Patients with metastatic colorectal cancer were divided into two groups according to serum vWF levels and the differences between these two groups were analyzed using chi2 test. Data on age, gender, performance status, location of primary tumor, extent of metastasis, site of metastases, histological differentiation, serum CEA and plasma vWF levels were analyzed to determine association with survival. Survival curves were constructed by Kaplan-Meier product limit method and the data was analyzed using log-rank test on a microcomputer. Multivariate analysis using the Cox's proportional hazards regression model was then performed to determine the independent prognostic indicators among all of the possible variables. Colorectal cancer patients were identified as having significantly higher plasma vWF concentrations than healthy controls (P<0.05). Moreover, higher vWF plasma levels were associated with advanced tumor stage (P<0.05) and the presence of multiple metastases (P = 0.014). Patients with lower vWF plasma levels (< or =160%) survived significantly longer than those with a higher plasma vWF level (log-rank test, P = 0.0043). By multivariate analysis, plasma vWF levels (P<0.001), the extent of metastasis (P = 0.012), and the performance status (P = 0.014) were identified as independent prognostic factors. Our data indicates that high plasma vWF concentrations correlate with advanced diseases and significantly poor prognosis of patients with metastatic colorectal carcinoma. It may serve as a potential biological marker of disease progression in these patients.


[Cancer patients in operative intensive care medicine].
Cancer is one of the leading causes of death worldwide. New targeted and individualized therapies and drugs provide a survival benefit for an increasing number of patients, but can also cause severe side effects. An increasing number of oncology patients are admitted to intensive care units (ICU) because of cancer-related complications or treatment-associated side effects. Postoperative care, respiratory distress and sepsis are the leading causes for admission. Tumor mass syndromes and tumor lysis may require urgent treatment. Traditional anticancer chemotherapy is associated with infections and immunosuppression. Newer agents are generally well-tolerated and side effects are mild or moderate, but overwhelming inflammation and autoimmunity can also occur. Cellular treatment, such as with chimeric antigen receptor modified T‑cells, monoclonal and bispecific antibodies targeting immune effectors and tumor cells are associated with cytokine release syndrome (CRS) with hypotension, skin reactions and fever. It is related to excessively high levels of inflammatory cytokines. Immune checkpoint inhibitors can lead to immune-related adverse events (IRAEs), such as colitis and endocrine disorders. Noninfectious respiratory complications, such as pneumonitis can also occur. Recent studies revealed that short-term and medium-term survival of cancer patients is better than previously expected. In this review article we summarize diagnostic and treatment strategies for common life-threatening complications and emergencies requiring ICU admission. Furthermore, strategies for rational admission policies are presented.


Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis.
Lymphotoxin beta (LTbeta), a cytokine produced by T cells and B cells, plays a central role in the normal development of lymph nodes and is critical in the formation of ectopic germinal center reactions in rheumatoid synovitis. Because resident fibroblast-like synoviocytes (FLS) express receptors for LTbeta, we examined the consequences of FLS activation by LTbeta. FLS from patients with rheumatoid arthritis were isolated and examined for the expression of LTbeta receptor. FLS were incubated with LTalpha1beta2 and assayed for the production of cytokines and chemokines and the up-regulation of adhesion molecules. Exposure of FLS to recombinant LTalpha1beta2 resulted in the production of multiple inflammatory cytokines and metalloproteinases, implicating FLS as amplifiers of the inflammatory process in the inflamed joint. Additionally, LTalpha1beta2 was found to up-regulate the expression of cell adhesion molecules, rendering FLS to efficient adhesion substrates for T cells. LTalpha1beta2 also induced production of the chemokines CCL2 and CCL5, which elicited transmigration activity of T cells. Upon stimulation with LTalpha1beta2, FLS did not acquire characteristics of follicular dendritic cells. These data document that FLS are involved in multiple stages of the inflammatory process, including the recruitment and retention of lymphocytes in the synovial microenvironment. We propose that the heterotypic interaction between LTbeta-producing lymphocytes and responding FLS contributes to the establishment of complex lymphoid microstructures, and that this may be one element that defines susceptibility of the synovial membrane to lymphoid organogenesis.


Applying Bogomolny's quantization method to generic classical systems.
The quantization method of Bogomolny [Nonlinearity 5, 805 (1992)] can potentially provide semiclassical estimates for energy levels of all bound states of arbitrary systems. This approach requires the formation of the transfer matrix TE as a function of energy E. Existing practical methods for calculating this matrix require a recalculation of many classical trajectories for each energy. This has hampered the application of Bogomolny's method to generic systems that do not possess special classical scaling properties. Generalizing earlier work [H. Barak and K. G. Kay, Phys. Rev. E 88, 062926 (2013)], we develop initial value representation formulas for TE that overcome this problem. These expressions are obtained from a generalized Herman-Kluk formula for the propagator that allows one to easily derive a family of semiclassical integral approximations for the Green's function that are, in turn, used to form the transfer matrix. Calculations for two-dimensional systems show that Bogomolny's method with the present expressions for TE produces accurate semiclassical energy levels from small transfer matrices.


Structural dissection of cyclin dependent kinases regulation and protein recognition properties.
Cyclin Dependent Kinases (CDKs) regulate the cell division cycle, apoptosis, transcription and differentiation in addition to functions in the nervous system. They are regulated by their cyclin partners and by a variety of additional protein effectors (inhibitors, kinases, phosphatases). Each CDK serves its function by means of specific protein recognition properties. These are also responsible for the differential regulation of CDKs/Cyclin couples involved in processes as different as cell cycle and transcription. The structural features determining general and specific properties for CDKs/Cyclin complexes are analyzed. They reside in an overall conserved architecture with divergent spots used by the complexes to present themselves to specific substrates or other protein effectors.


Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury.
Traumatic brain injury (TBI) is one of the leading causes of disability worldwide and a prominent risk factor for neurodegenerative diseases. The expansion of nervous tissue damage after the initial trauma involves a multifactorial cascade of events, including excitotoxicity, oxidative stress, inflammation, and deregulation of sphingolipid metabolism that further mitochondrial dysfunction and secondary brain damage. Here, we show that a posttranscriptional activation of an acid sphingomyelinase (ASM), a key enzyme of the sphingolipid recycling pathway, resulted in a selective increase of sphingosine in mitochondria during the first week post-TBI that was accompanied by reduced activity of mitochondrial cytochrome oxidase and activation of the Nod-like receptor protein 3 inflammasome. TBI-induced mitochondrial abnormalities were rescued in the brains of ASM KO mice, which demonstrated improved behavioral deficit recovery compared with WT mice. Furthermore, an elevated autophagy in an ASM-deficient brain at the baseline and during the development of secondary brain injury seems to foster the preservation of mitochondria and brain function after TBI. Of note, ASM deficiency attenuated the early stages of reactive astrogliosis progression in an injured brain. These findings highlight the crucial role of ASM in governing mitochondrial dysfunction and brain-function impairment, emphasizing the importance of sphingolipids in the neuroinflammatory response to TBI.


Comparison of the nuclear organiser region activity in four taxa of the family Canidae.
Four species of the family Canidae were cytogenetically studied. The activity of NORs was detected with the use of silver staining. The number of NORs was characteristic for a given karyotype. For the dog found on autosomes 7, 17, 20 and on sex chromosome (Y), for the racoon dog on autosomes 1, 4, 13 and on sex chromosome (Y), for the silver fox only on autosomes 8, 9, 13 and for the blue fox on autosomes 13, 15, 17, 18, 20 and 22. The results demonstrate that NOR activity is similar in all the analysed species of the Canidae. Simultaneously, NOR activity for a medium-sized chromosome pair is distinctly higher than for two other autosome pairs (the longest and the smallest pair). Considerable variability was observed within individuals.


Interindividual and Regional Variability in Drug Transporter Abundance at the Human Blood-Brain Barrier Measured by Quantitative Targeted Proteomics.
For in vitro to in vivo extrapolation (IVIVE) of brain distribution of drugs that are transported at the human blood-brain barrier (BBB), it is important to quantify the interindividual and regional variability of drug transporter abundance at this barrier. Therefore, using quantitative targeted proteomics, we compared the abundance of adenosine triphosphate-binding cassette and solute carrier transporters in brain microvascular endothelial cells (BMECs) isolated from postmortem specimens of two matched brain regions, the occipital (Brodmann Area (BA)17) and parietal (BA39) lobe, from 30 adults. Of the quantifiable transporters, the abundance ranked: glucose transporter (GLUT)1 > breast cancer resistance protein > P-glycoprotein (P-gp) > equilibrative nucleoside transporter (ENT)1 > organic anion-transporting polypeptide (OATP)2B1. The abundance of multidrug resistance protein 1/2/3/4, OATP1A2, organic anion transporter (OAT)3, organic cation transporter (OCT)1/2, OCTN1/2, or ENT2 was below the limit of quantification. Transporter abundance per gram of tissue (scaled using GLUT1 abundance in BMEC vs. brain homogenate) in BA17 was 30-42% higher than BA39. The interindividual variability in transporter abundance (percentage of coefficient of variation (%CV)) was 35-57% (BA17) and 27-46% (BA39). These data can be used in proteomics-informed bottom-up IVIVE to predict human brain drug distribution.


Development of the Pica, ARFID, and Rumination Disorder Interview, a multi-informant, semi-structured interview of feeding disorders across the lifespan: A pilot study for ages 10-22.
Avoidant/restrictive food intake disorder (ARFID), pica, and rumination disorder (RD) were added to the revised DSM-5 Feeding and Eating Disorders chapter in 2013. We developed a structured interview-the Pica, ARFID, and Rumination Disorder Interview (PARDI)-to assess the presence and severity of these diagnoses for evaluation and treatment planning in clinical and research settings. Here, we describe the development of the PARDI and provide a preliminary report on feasibility, acceptability, reliability, and validity in relation to ARFID. We created an initial item pool from existing measures of similar constructs and clinical experience. The PARDI includes items assessing the level of endorsement and overall severity of common ARFID features organized into profiles (i.e., sensory sensitivity, lack of interest in eating, and fear of aversive consequences) and algorithms for diagnosing ARFID, pica, and RD. We collected initial psychometric data from participants (10-22 years) with ARFID (n = 39), clinically significant avoidant/restrictive eating (n = 8), and healthy controls (n = 10). On average, the PARDI took 39 min to complete and was acceptable to participants. All subscales achieved internal consistency greater ≥0.77, and inter-rater reliability for the ARFID diagnosis was moderate (κ = 0.75). Individuals with ARFID scored significantly higher than healthy controls on ARFID severity and ARFID profiles. The PARDI appears acceptable to respondents and preliminary evidence of reliability and validity has been demonstrated in an initial sample. Larger-scale validation studies are currently underway. The PARDI is freely available to clinicians and researchers.


Dietary Balance Index-07 and the Risk of Anemia in Middle Aged and Elderly People in Southwest China: A Cross Sectional Study.
A balanced diet is essential to achieve and maintain good health. In this study, we assessed diet quality of middle aged and elderly people based on Chinese Diet Balance Index-07 (DBI-07) and explored the associations between DBI-07 and anemia. Data analyzed for this study was from the 2010-2012 National Nutrition and Health Survey in Yunnan province, southwest China (n = 738, aged 50-77 years). Dietary recalls over there consecutive days were done in a face-to-face interview. The scores of DBI-07 for each component and three DBI-07 indicators ((Lower Bound Score (LBS), Higher Bound Score (HBS), Diet Quality Distance (DQD)) were calculated according to compliance with the Dietary Guidelines for Chinese residents. Hemoglobin (Hb) concentration was determined using the cyanmethemoglobin method. Univariate and multivariate linear regression models were used to explore the associations between DBI-07 indicators and anemia, as well as scores of DBI-07 components and Hb level. The sample included 336 men and 402 women. Inadequate intakes of vegetables, fruits, dairy, soybean, eggs, fish and excessive intakes of cereals, meat, cooking oil, salt were both common. 91.3% of the participants had moderate or high levels of inadequate food intake, while 37.7% had moderate or high levels of excessive food intake. The mean Hb was 14.2 ± 1.7 g/dL, with a prevalence of anemia of 13.0%. Subjects with high LBS and DQD were more likely to be anemic (all p < 0.05). After adjustment for potential confounders, there were positive correlations between Hb level and the intakes of vegetables and soybean (βvegetables = 1.04, p < 0.01; βsoybean = 0.82, p = 0.04). In conclusion, dietary imbalance and anemia are common in middle aged and elderly population in southwest China and inadequate intakes of vegetables and soybean may increase the risk of anemia.


Mitochondrial AKAP1 supports mTOR pathway and tumor growth.
Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy.


Impaired atrial contraction in patients with atrial flutter and gradual recovery after cardioversion.
The risk of thromboembolism after cardioversion of atrial flutter is controversial. The present study provides evidence for blood stasis in the atria of patients with atrial flutter and for gradual recovery of atrial contraction after cardioversion, which justifies prophylactic treatment at cardioversion, as for atrial fibrillation. We examined atrial thrombi and peak flow velocity in the left atrial appendage as an index of blood stasis in 5 consecutive patients with atrial flutter. Transesophageal echocardiography revealed a thrombus in 1 patient, and peak flow velocity in the left atrial appendage was inversely correlated with left atrial dimension (r = -0.90, p < 0.05). After restoration of sinus rhythm, transmitral flow velocity in late diastole was also examined to evaluate the recovery of atrial contraction. The recovery of transmitral flow velocity the next day and 1 week after cardioversion was correlated with flow velocity in the left atrial appendage before cardioversion (r = 0.89, p < 0.05; r = 0.97, p < 0.01, respectively). These findings suggest that some patients with atrial flutter have impaired atrial contraction and that prolonged impairment after cardioversion is also possible. Atrial enlargement and low flow velocity in the atrial appendage were predictive factors for such patients.


Stereotactic mesencephalic tractotomy for the relief of thalamic pain.
Twenty-seven patients with pain of central origin following cerebral hemisphere or brain stem infarction underwent stereotactic mesencephalic tractotomy. Twenty-one (77.8%) were pain free or significantly improved at discharge. Twenty-four were available for later review and 1p (66.7%) reported relief up to 5 years later. The target site was revised after the first 14 patients, reducing the number obtaining long term relief (lesion I, at the level of the superior colliculus--75%; lesion II, at the level of the inferior colliculus--58.3%), but substantially decreasing the incidence of disorders of ocular function from 83.3% to 16.7%.


Effects of gravitational perturbation on the expression of genes regulating metabolism in Jurkat cells.
Gravitational pertubation altered gene expression and increased glucose consumption in spaceflown Jurkat cells. The purpose of this study was to determine if the acceleration experienced during launch was responsible for these changes. In ground-based studies, cells were subjected to typical launch centrifugal acceleration (3g of force for eight minutes) and centrifugal force of 90g for five minutes (commonly used to sediment cells) in a laboratory centrifuge. Controls consisted of static cultures. Gene expression was analyzed by RT-PCR. pH and glucose concentrations were evaluated to monitor metabolic changes. Comparison with controls indicated no significant change in pH or glucose use. Gene expression of Jurkat cells subjected to 3g or 90g of force was altered for only two genes out of seven tested. This research suggests that the changes observed in Jurkat cells flown on STS-95 were not a result of launch acceleration but to other conditions experienced during space flight.


Economic evaluation of a Bayesian model to predict late-phase success of new chemical entities.
To evaluate the economic impact of a Bayesian network model designed to predict clinical success of a new chemical entity (NCE) based on pre-phase III data. We trained our Bayesian network model on publicly accessible data on 503 NCEs, stratified by therapeutic class. We evaluated the sensitivity, specificity and accuracy of our model on an independent data set of 18 NCE-indication pairs, using prior probability data for the antineoplastic NCEs within the training set. We performed Monte Carlo simulations to evaluate the economic performance of our model relative to reported pharmaceutical industry performance, taking into account reported capitalized phase costs, cumulative revenues for a postapproval period of 7 years, and the range of possible false negative and true negative rates for terminated NCEs within the pharmaceutical industry. Our model predicted outcomes on the independent validation set of oncology agents with 78% accuracy (80%sensitivity and 76% specificity). In comparison with the pharmaceutical industry's reported success rates, on average our model significantly reduced capitalized expenditures from $727 million/successful NCE to $444 million/successful NCE (P < 0.001), and significantly improved revenues from $347 million/phase III trial to $507 million/phase III trial (P < 0.001) during the first 7 years post launch. These results indicate that our model identified successful NCEs more efficiently than currently reported pharmaceutical industry performances. Accurate prediction of NCE outcomes is computationally feasible, significantly increasing the proportion of successful NCEs, and likely eliminating ineffective and unsafe NCEs.


Influence of Clinical Parameters on the Primary Stability of a Tapered Dental Implant: A Retrospective Analysis.
The aim of this study was to investigate the influence of different clinical parameters on the primary stability of a variable thread tapered implant system with a focus on surgical undersizing protocols. This retrospective study evaluated patients who received NobelActive implants in a single institution. The relationship between the independent variables, bone quality, implant diameter, implant length, implantation time, region of the jaw, and surgical undersizing protocol, and the dependent variable, maximum insertion torque, was investigated. Statistical analysis was conducted using analysis of variance (ANOVA) and multiple linear regression. A total of 1,292 implants placed in 574 fully or partially edentulous patients were evaluated. For the total sample size, without further differentiation between bone qualities, statistically significantly higher primary stability values were shown for an 8% to 9% undersized group (50.33 ± 17.16 Ncm), compared with a 16% undersized group (41.88 ± 17.63 Ncm), a 20% undersized group (33.65 ± 15.78 Ncm), a 26% to 28% undersized group (34.53 ± 15.49 Ncm), and a 35% to 44% undersized group (32.78 ± 18.80 Ncm). No statistical differences were found for undersizing protocols in bone quality 4. Bone quality had the highest influence on primary stability (Welch-Test F(3, 65.57) = 119.48, P < .001, η2 = .20). Contrary to the other investigated independent variables, no statistically significant differences in primary stability were found for the different implantation times. Undersizing protocols exceeding 8% to 9% do not seem to enhance primary stability values. Further studies are needed to investigate the biologic consequences of undersizing, including the impact of implant design characteristics.


Perioperative and Oncological Outcomes of Robotic Versus Open Pancreaticoduodenectomy in Low-Risk Surgical Candidates: A Multicenter Propensity Score-Matched Study.
This study aimed to perform a multicenter comparison between robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD). Previous comparisons of RPD versus OPD have only been carried out in small, single-center studies of variable quality. Consecutive patients who underwent RPD (n = 1032) or OPD (n = 1154) at 7 centers in China between July 2012 and July 2020 were included. A 1:1 propensity score matching (PSM) was performed. After PSM, 982 patients in each group were enrolled. The RPD group had significantly lower estimated blood loss (EBL) (190.0 vs 260.0 mL; P < 0.001), and a shorter postoperative 1length of hospital stay (LOS) (12.0 (9.0-16.0) days vs 14.5 (11.0-19.0) days; P < 0.001) than the OPD group. There were no significant differences in operative time, major morbidity including clinically relevant postoperative pancreatic fistula (CR-POPF), bile leakage, delayed gastric emptying, postoperative pancreatectomy hemorrhage (PPH), reoperation, readmission or 90-day mortality rates. Multivariable analysis showed R0 resection, CR-POPF, PPH and reoperation to be independent risk factors for 90-day mortality. Subgroup analysis on patients with pancreatic ductal adenocarcinoma (PDAC) (n = 326 in each subgroup) showed RPD had advantages over OPD in EBL and postoperative LOS. There were no significant differences in median disease-free survival (15.2 vs 14.3 months, P = 0.94) or median overall survival (24.2 vs 24.1 months, P = 0.88) between the 2 subgroups. RPD was comparable to OPD in feasibility and safety. For patients with PDAC, RPD resulted in similar oncologic and survival outcomes as OPD.


[Induction of transcription through the scs insulator leads to abnormal development of Drosophila melanogaster].
A regulatory element named scs is one of the first insulators discovered in Drosophila, which was found on the boundary of the hsp70 domain. The 993-bp scs insulator contains two promoters at the ends and two polyadenylation signals located in the same orientation in the central part of the insulator. In the Drosophila transgenic lines, induction of a strong transcription through the scs insulator only in the direction that coincides with the direction of the two polyadenylation sites activity results in multiple phenotypic defects of the Drosophila development and embryonic lethality. A similar effect was not observed upon testing of other known Drosophila insulators.


The effects of intravaginal clindamycin and metronidazole therapy on vaginal mobiluncus morphotypes in patients with bacterial vaginosis.
The objective of this study was to compare the effects of treatments for bacterial vaginosis (BV) on vaginal Mobiluncus morphotypes. Analyses were performed on Mobiluncus scores from similarly conducted studies evaluating clindamycin vaginal single-dose cream (CVSDC) or metronidazole vaginal gel (MVG) in 55 patients with BV and with Mobiluncus morphotypes at baseline. Both treatment groups demonstrated significant reductions in Mobiluncus score. However, the Mobiluncus score at test-of-cure was lower in the CVSDC than in the MVG group (P=0.0471). More patients in the CVSDC group than in the MVG group achieved microbiologic (57.5% vs. 26.7%; P=0.04), clinical (57.5% vs. 26.7%; P=0.04), and therapeutic cures of BV (45.0% vs. 20.0%; P=0.09). Clindamycin reduces vaginal Mobiluncus morphotypes to a greater extent than metronidazole in patients with BV; this correlates with a higher BV cure rate.


Effective robotic assistive pattern of treadmill training for spinal cord injury in a rat model.
The purpose of the present study was to establish an effective robotic assistive stepping pattern of body-weight-supported treadmill training based on a rat spinal cord injury (SCI) model and assess the effect by comparing this with another frequently used assistive stepping pattern. The recorded stepping patterns of both hind limbs of trained intact rats were edited to establish a 30-sec playback normal rat stepping pattern (NRSP). Step features (step length, step height, step number and swing duration), BBB scores, latencies, and amplitudes of the transcranial electrical motor-evoked potentials (tceMEPs) and neurofilament 200 (NF200) expression in the spinal cord lesion area during and after 3 weeks of body-weight-supported treadmill training (BWSTT) were compared in rats with spinal contusion receiving NRSP assistance (NRSPA) and those that received manual assistance (MA). Hind limb stepping performance among rats receiving NRSPA during BWSTT was greater than that among rats receiving MA in terms of longer step length, taller step height, and longer swing duration. Furthermore a higher BBB score was also indicated. The rats in the NRSPA group achieved superior results in the tceMEPs assessment and greater NF200 expression in the spinal cord lesion area compared with the rats in the MA group. These findings suggest NRSPA was an effective assistive pattern of treadmill training compared with MA based on the rat SCI model and this approach could be used as a new platform for animal experiments for better understanding the mechanisms of SCI rehabilitation.


[Psoriasis: an update].
Psoriasis is a frequent dermatosis observed in 2 to 3% of people. It usually begin at the second decade of age but can also affect children. Diagnosis is often easily made by clinical exam. How ether many problems characterise this pathology and are not actually resolved: problems about epidemiology, etiology, treatment and psychological effects.


[Physicians today].
The last few years have witnessed radical changes in medical practices due to scientific and technological developments, the population's demands, the evolution of the economy, the optimisation of resources, the Media, not forgetting the major ethical, legal and political aspects, which have changed considerably in just a few years. Basic training, specialised training and ongoing training must allow doctors to assume many of these changes, although in general in should be they who are willing to put such changes into practice. Education and training should be modified to make it easier and faster to assume these changes. Medicine is no longer what it used to be: instead of being limited, knowledge is now boundless, instead of working alone, doctors now work in teams, instead of only the doctor having the information, patients now have it too. There has been a move from the ethics of welfare to the ethics Of autonomy, from problem-free spending to cost containment, from the demand for relief to the demand for treatment and healing, from a call for health to a call for quality of health, from non-judicialisation, and so on and so forth. All these factors have clearly affected the structure of medicine, and it is not surprising that nowadays there is more talk about the prestige of medicine that the prestige of the doctor, as occurred not so many years ago. There is really no substitute for individual attitudes to this situation. The article contains certain considerations about how current changes are affecting doctor's attitudes and the need not only to accept the change but also to lead it. The competitive doctor of today must meet a broad spectrum of requirements, ranging from initiative and flexibility to technological know-how-and capacity. Nowadays society is moving towards a situation in which it not only demands and expects these conditions from its leaders but also from all doctors. Patients have an increasingly higher level of education and, as such, are becoming more demanding because they have tools with which to compare and demand more from doctors.


Anaphylatoxin signaling activates macrophages to control intracellular Rickettsia proliferation.
Pathogenic Rickettsia species proliferate within the cytoplasm of permissive host cells in vivo. The cytoplasm of these host cells is adequate to support the complex metabolic and physiological needs for Rickettsia growth. However, a dramatic host/pathogen interplay occurs when Rickettsia encounter innate immune cells, whereby the bacteria can proliferate as normal or the host can restrict bacterial growth. This interplay is most divergent within myeloid host cells, where intra- and extracellular factors can produce either successful Rickettsia parasitism or innate immune control of bacterial proliferation. With the prior knowledge that the mammalian complement system is activated during mammalian infection, we sought to determine if extracellular complement activation and anaphylatoxin signaling can modify the fate of Rickettsia within mononuclear host cells. Results indicate that supplementation of growth media with either C3a or C5a anaphylatoxin peptides is sufficient for many myeloid cells to control the proliferation of multiple different Rickettsia species. Chemical or genetic disruption of anaphylatoxin signaling or anaphylatoxin receptors eliminates complement-induced restriction of bacterial proliferation. Finally, anaphylatoxin signaling modifies macrophage physiology by inducing inflammatory phenotypes that ultimately control the intracellular proliferation of these pathogens.IMPORTANCEPathogenic Rickettsia species are extremely dangerous bacteria that grow within the cytoplasm of host mammalian cells. In most cases, these bacteria are able to overpower the host cell and grow within the protected environment of the cytoplasm. However, a dramatic conflict occurs when Rickettsia encounter innate immune cells; the bacteria can "win" by taking over the host, or the bacteria can "lose" if the host cell efficiently fights the infection. This manuscript examines how the immune complement system is able to detect the presence of Rickettsia and alert nearby cells. Byproducts of complement activation called anaphylatoxins are signals that "activate" innate immune cells to mount an aggressive defensive strategy. This study enhances our collective understanding of the innate immune reaction to intracellular bacteria and will contribute to future efforts at controlling these dangerous infections.


Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy.
Two siblings from consanguineous parents died perinatally with a condition characterized by generalized hypotonia, respiratory insufficiency, arthrogryposis, microcephaly, congenital brain malformations and hyperglycinemia. Catalytic activities of the mitochondrial respiratory complexes I and II were deficient in skeletal muscle, a finding suggestive of an inborn error in mitochondrial biogenesis. Homozygosity mapping identified IBA57 located in the largest homozygous region on chromosome 1 as a culprit candidate gene. IBA57 is known to be involved in the biosynthesis of mitochondrial [4Fe-4S] proteins. Sequence analysis of IBA57 revealed the homozygous mutation c.941A > C, p.Gln314Pro. Severely decreased amounts of IBA57 protein were observed in skeletal muscle and cultured skin fibroblasts from the affected subjects. HeLa cells depleted of IBA57 showed biochemical defects resembling the ones found in patient-derived cells, including a decrease in various mitochondrial [4Fe-4S] proteins and in proteins covalently linked to lipoic acid (LA), a cofactor produced by the [4Fe-4S] protein LA synthase. The defects could be complemented by wild-type IBA57 and partially by mutant IBA57. As a result of the mutation, IBA57 protein was excessively degraded, an effect ameliorated by protease inhibitors. Hence, we propose that the mutation leads to partial functional impairment of IBA57, yet the major pathogenic impact is due to its proteolytic degradation below physiologically critical levels. In conclusion, the ensuing lethal complex biochemical phenotype of a novel metabolic syndrome results from multiple Fe/S protein defects caused by a deficiency in the Fe/S cluster assembly protein IBA57.


Evidence of agomelatine's antidepressant efficacy: the key points.
Depressive disorders are of the highest socioeconomic and health-economic importance, as they are the psychiatric disorders that most frequently cause psychosocial disability. Despite the progress that has been made, currently available pharmacotherapies for depression still have a limited antidepressant efficacy with a delayed onset of several weeks, and still cause side effects; these unmet needs represent important reasons to continue to search for novel treatment options. A disorganization of circadian rhythms has been suggested to play an important role in the pathophysiology of major depression, and complaints regarding disturbed sleep are frequent in depressed patients. As endogenous melatonin secretion underlies the regulation of circadian rhythms, compounds with activity at melatonergic receptors have been proposed as potential novel therapeutics. Agomelatine (S-20098), a compound with agonistic properties at MT1 and MT2 receptors and antagonistic properties at the 5-HT2C receptor, has been shown preclinically to exhibit robust antidepressant effects in several experimental paradigms. Clinical trials, including phase III studies, have now demonstrated the superior efficacy of agomelatine in comparison with placebo, and a similar efficacy in comparison with active comparators, for the treatment of major depression. Agomelatine was even effective in severely depressed patients. In all studies published so far, agomelatine was found to be safe and its overall tolerability profile was superior to that of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors.


Negative emotions in cancer care: do oncologists' responses depend on severity and type of emotion?
To examine how type and severity of patients' negative emotions influence oncologists' responses and subsequent conversations. We analyzed 264 audio-recorded conversations between advanced cancer patients and their oncologists. Conversations were coded for patients' expressions of negative emotion, which were categorized by type of emotion and severity. Oncologists' responses were coded as using either empathic language or blocking and distancing approaches. Patients presented fear more often than anger or sadness; severity of disclosures was most often moderate. Oncologists responded to 35% of these negative emotional disclosures with empathic language. They were most empathic when patients presented intense emotions. Responding empathically to patients' emotional disclosures lengthened discussions by an average of only 21s. Greater response rates to severe emotions suggest oncologists may recognize negative emotions better when patients express them more intensely. Oncologists were least responsive to patient fear and responded with greatest empathy to sadness. Oncologists may benefit from additional training to recognize negative emotions, even when displayed without intensity. Teaching cancer patients to better articulate their emotional concerns may also enhance patient-oncologist communication.


Genetic parameters of natural antibody isotypes and survival analysis in beak-trimmed and non-beak-trimmed crossbred laying hens.
Natural antibodies (NAb) are important humoral components of innate immunity. As the first line of defense, NAb provide protection against infection and support adaptive immunity. An earlier study indicated that serum levels of NAb isotypes IgM and IgG at a young age were predictive for survival in non-beak-trimmed purebred laying hens during the laying period. In the present study, genetic parameters of NAb isotypes were estimated and relationships between survival and NAb isotypes levels in crossbred laying hens were investigated. In total, 1,555 beak-trimmed and 1,169 non-beak-trimmed crossbred laying hens were used. Genetic parameters of IgM and IgG titers binding keyhole limpet hemocyanin at 24 wk of age were estimated with a linear animal model. The heritabilities of NAb isotypes IgG and IgM were 0.21 (SE = 0.04) and 0.26 (SE = 0.04), respectively. The genetic correlation between IgG and IgM isotypes was 0.43 (SE = 0.11). These results indicated that NAb isotype titers were heritable traits in the crossbred laying hens. Both NAb isotypes can be selected for simultaneously because the detected positive genetic correlation (0.43, SE = 0.11) between them is positive. Both row and level of the cage were indicated to be associated environmental factors for NAb isotype titers. Different from an earlier study with purebred hens, survival analysis showed no significant associations of survival with NAb isotype titers in beak-trimmed or non-beak-trimmed crossbred hens. Non-health-related causes of mortality, especially in birds with intact beaks, overruled the anticipated relationships between NAb isotype titers and survival.


Evaluation of emphysema in patients with asthma using high-resolution CT.
Bronchial asthma is a clinical syndrome characterized by reversibility of airway obstruction. However, many asthmatics have evidence of residual airway obstruction. It has become evident that the repair of the chronic inflammatory process can lead to various irreversible changes. It is generally accepted that the most common cause for the change is cigarette smoking but it is controversial whether asthma progresses to emphysema. High resolution computed tomography (HRCT) is more sensitive and more accurate than chest plain films in determining the type and extent of emphysema. This study was carried out to determine whether asthma can be a cause of emphysema without the effect of cigarette smoking and to evaluate clinical characteristics in asthmatics with emphysema. We studied 58 asthmatic patients with reversible airway obstruction and evaluated the presence of emphysema using HRCT and pulmonary function test. According to HRCT findings, they were divided into 2 groups: Asthmatics with emphysema and the ones without emphysema. Of the 58 patients, 7 were revealed to have emphysema. (1) 6 asthmatics with emphysema were smokers, but one patient was a nonsmoker. (2) Highly significant differences between asthmatics with and without emphysema were found in cigarette smoking (p < 0.01) and smoking consumption (p < 0.01). (3) There were no significant differences in the duration of asthma, age or sex between patients with and without emphysema. (4) There were no significant differences in FEV1(%), FEV1/FVC (%), diffusing capacity for carbon monoxide (DLco) (%) and DLco/alveolar volume between patients with and without emphysema (5) Differences between asthma patients without emphysema and those with emphysema were found to be significant in bronchial wall thickness (p < 0.05) and in total Ig E levels (p = 0.07). These results indicate that smoking is a main factor in causing emphysema in asthmatics.


Prolonging the interval from ovarian hyperstimulation to laparoscopic ovum pick-up improves oocyte yield, quality, and developmental competence in goats.
The objective was to evaluate the effect of the interval between ovarian hyperstimulation and laparoscopic ovum pick-up (LOPU) on quality and developmental competence of goat oocytes before and after in vitro maturation (IVM) and intracytoplasmic sperm injection (ICSI). Estrus was synchronized with an intravaginal insert containing 0.3g progesterone (CIDR) for 10d, combined with a luteolytic treatment of 125 microg cloprostenol 36 h prior to CIDR removal. Ovaries were hyperstimulated with 70 mg FSH and 500 IU hCG given im 36, 60, or 72 h prior to LOPU (n=15, 16, and 7 does, respectively). For these groups, oocyte retrieval rates (mean+/-S.E.M.) were 24.7+/-2.9, 54.5+/-4.7, and 82.8+/-4.6% (P<0.001), and the proportions of cumulus-oocyte complexes (COC) with more than five layers of cumulus cells were 29.7+/-8.3, 37.6+/-6.9, and 37.3+/-7.0% (P<0.001). The proportion of IVM oocytes was highest at 72 h (82.1+/-2.8%; P<0.05), with no significant difference between 36 and 60 h (57.3+/-8.9% and 69.0+/-8.4%). Cleavage rates of ICSI embryos were 4.2+/-4.2, 70.9+/-8.4, and 78.9+/-8.2% with LOPU 36, 60, and 72 h post FSH/hCG (P<0.01), with a lower proportion of Grade-A embryos (P<0.05) following LOPU at 36 h compared to 60 and 72 h (29.7+/-8.3%, 37.6+/-6.9%, and 37.3+/-7.0%). In summary, a prolonged interval from FSH/hCG to LOPU improved oocyte retrieval rate and oocyte quality. Therefore, under the present conditions, LOPU 60 or 72 h after FSH/hCG optimized yields of good-quality oocytes for IVM and embryo production in goats.


Vibrational circular dichroism and theoretical study of the conformational equilibrium in (-)-S-nicotine.
We report an extensive study of the molecular and electronic structure of (-)-S-nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution-state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (-)-S-nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (-)-S-nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three-dimensional structure of chiral samples and prove their suitability for the elucidation of solution-state conformer distribution.