ATP activation of parathyroid hormone cleavage catalyzed by cathepsin D from bovine kidney.
The acid protease which is activated by ATP and which catalyzes production of fragments of parathyroid hormone similar to those produced in vivo was shown to be cathepsin D. Purified cathepsin D from bovine kidney and spleen is activated by ATP and other nucleoside triphosphates, and to a much lesser extent by nucleoside diphosphates and pyrophosphate. These findings suggest that cathepsin D may be involved in parathyroid hormone metabolism in vivo and that this lysosomal enzyme may be regulated by the energy status of the cell.


Fluorescent D-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation.
Modification of essential bacterial peptidoglycan (PG)-containing cell walls can lead to antibiotic resistance; for example, β-lactam resistance by L,D-transpeptidase activities. Predatory Bdellovibrio bacteriovorus are naturally antibacterial and combat infections by traversing, modifying and finally destroying walls of Gram-negative prey bacteria, modifying their own PG as they grow inside prey. Historically, these multi-enzymatic processes on two similar PG walls have proved challenging to elucidate. Here, with a PG-labelling approach utilizing timed pulses of multiple fluorescent D-amino acids, we illuminate dynamic changes that predator and prey walls go through during the different phases of bacteria:bacteria invasion. We show formation of a reinforced circular port-hole in the prey wall, L,D-transpeptidaseBd-mediated D-amino acid modifications strengthening prey PG during Bdellovibrio invasion, and a zonal mode of predator elongation. This process is followed by unconventional, multi-point and synchronous septation of the intracellular Bdellovibrio, accommodating odd- and even-numbered progeny formation by non-binary division.


Apparatus design and behavioural testing protocol for the evaluation of spatial working memory in mice through the spontaneous alternation T-maze.
Spatial working memory can be assessed in mice through the spontaneous alternation T-maze test. The T-maze is a T-shaped apparatus featuring a stem (start arm) and two lateral goal arms (left and right arms). The procedure is based on the natural tendency of rodents to prefer exploring a novel arm over a familiar one, which induces them to alternate the choice of the goal arm across repeated trials. During the task, in order to successfully alternate choices across trials, an animal has to remember which arm had been visited in the previous trial, which makes spontaneous alternation T-maze an optimal test for spatial working memory. As this test relies on a spontaneous behaviour and does not require rewards, punishments or pre-training, it represents a particularly useful tool for cognitive evaluation, both time-saving and animal-friendly. We describe here in detail the apparatus and the protocol, providing representative results on wild-type healthy mice.


Understanding the Roles of the NF-κB Pathway in Regulatory T Cell Development, Differentiation and Function.
The nuclear factor of kappaB (NF-κB) pathway has emerged as an important regulator of gene expression in CD4(+) regulatory T cells. Here, we review various aspects of the roles NF-κB signaling plays in the development and function of Tregs.


Amyloid precursor protein (APP) in the striatum in Alzheimer's disease: an immunohistochemical study.
Increasing recognition of diffuse plaques has raised questions about the differences between diffuse and neuritic plaques, particularly in regard to the role of amyloid precursor protein (APP) processing in their formation. To address this issue, corpus striatum (containing almost exclusively diffuse plaques) and cerebral cortex (containing an admixture of plaque types) from patients with Alzheimer's disease (AD) were examined immunohistochemically with antibodies to domain-specific sites of APP (N-terminal, C-terminal, beta A4-related, isoform-specific, and other epitopes). Striatal plaques labeled strongly with beta A4 antibodies as did cortical plaques in AD and the occasional diffuse plaques in cortex from nondemented elderly controls. Weak labeling of some cortical neuritic plaques but not diffuse plaques was observed with antibodies directed against other APP epitopes. Electron microscopy of diffuse plaque-rich striatum in AD cases revealed only rare degenerating neurites without apparent fibrillar amyloid; no changes were noted in the plaque-free striatum of controls. These results suggest that antibodies to beta A4 recognize not only fibrillar amyloid of neuritic plaques but also antigenic determinants of diffuse plaques which lack fibrillar amyloid. Furthermore, the finding that antibodies to non-A4 domains of APP labeled only cortical but not striatal plaques suggests that APP processing mechanisms in cortical and striatal tissues may differ.


Molecule Ideation Using Matched Molecular Pairs.
Matched Molecular Pair Analysis (MMP) is a very important tool during the lead optimization stage in drug discovery. The usefulness of this tool in the lead optimization stage has been discussed in several peer-reviewed articles. The application of MMP in Molecule generation is relatively new. This brings several challenges one of them being the need to encode contextual information into the transforms. In this chapter, we discuss how we use MMPs as a molecule generation method and how does it compare with other molecular generators.


Detection of domoic acid in rat serum and brain by direct competitive enzyme-linked immunosorbent assay (cELISA).
In 1987 a large-scale incident of human poisoning in Canada was traced to commercial mussels contaminated with domoic acid (DOM). Since then, routine screening of shellfish domoic acid content has been carried out using a variety of assays, with liquid chromatography using ultraviolet absorbance detection (LC-UV) or mass spectrometric detection (LC-MS) being the currently accepted standard methodologies. Recently, a highly specific competitive enzyme-linked immunosorbent assay (cELISA) has been developed for the detection and analysis of DOM in commercial shellfish, but its accuracy relative to LC methods has not been independently verified in mammalian tissues. In this study we demonstrate that measurement of rat serum DOM concentration by cELISA gives a good correlation (r2 = 0.993) across a broad range of concentrations when compared to LC-MS analysis, with only a small (15%) overestimation of sample DOM content. In addition, we have developed an extraction method for analysis of DOM in rat brain by cELISA which yields complete recovery across a range of sample dilutions.


Prostaglandin metabolism by human testis.
Human testis preparations appear to carry out both the synthesis and turnover of prostaglandins. Prostaglandins and prostaglandin metabolites were extracted from whole tissue. Testis microsomes converted both endogenous and exogenous substrate to prostaglandins. Microsomal prostaglandin biosynthesis was inhibited by indomethacin. Prostaglandin E2-9-ketoreductase was present in both the cytosolic and microsomal fractions of human testis. Prostaglandin metabolism by human testis has not previously been reported.


Clinical Outcomes Following Simple or Complex Stenting for Coronary Bifurcation Lesions: A Meta-Analysis.
Stent placement remains a challenge for coronary bifurcation lesions. While both simple and complex stenting strategies are available, it is unclear which one results in better clinical outcomes. This meta-analysis aims to explore the long-term prognosis following treatment with the 2 stenting strategies. Randomized controlled trials found from searches of the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were included in this meta-analysis. The complex stent placement strategy was identified as the control group, and the simple stent placement strategy was identified as the experimental group. Data were synthesized with a random effects model. The quality of the randomized controlled trials was assessed by Jadad scale scores. The clinical endpoints at 6 months, 1 year, and 5 years were analyzed. A total of 11 randomized controlled trials met the inclusion criteria. A total of 2494 patients were included in this meta-analysis. The odds ratio [OR] of the major adverse cardiac events (MACEs) at 6 months was 0.85 (95% confidence interval [CI] 0.53-1.35; P = .49, I 2 = 0%). The OR of the MACEs at 1 year was 0.61 (95% CI 0.36-1.05; P = .08, I 2 = 0%). The OR of the MACEs at 5 years was 0.69 (95% CI 0.51-0.92; P = .01, I 2 = 0%). Compared with the complex strategy, the simple strategy was associated with a lower incidence of MACEs at 5 years. Compared to the complex stenting strategy, the simple stenting strategy can better reduce the occurrence of long-term MACEs for coronary bifurcation lesions.


Response of MTX-resistant V79 cells to some DNA-damaging agents.
Three methotrexate (MTX)-resistant clones selected at 200 nM MTX have been isolated from UV-irradiated V79 cells and were marked M1, M2 and M3. Two further clones were also isolated by gradually exposing M1 to higher concentrations of MTX and marked M4 and M5, isolated at 1200 nM and 2400 nM MTX respectively. The frequency of the induction of MTX-resistant clones by UV light was found to increase significantly on treatment of the irradiated cells with either 3-aminobenzamide or caffeine. The resistant clones had the same sensitivity as the parental cells to UV light, but were resistant to gamma-rays, MNNG and H2O2. In MTX-resistant cells low-dose H2O2-induced repair function was absent. UV-induced mutation at the HGPRT locus was the same in MTX-resistant as sensitive cells, whereas for MNNG-induced mutation it was higher in resistant cells. The rate of SCE induction by UV light was higher in MTX-resistant cells compared to the parental ones, but was not significantly different for induction by MNNG and H2O2.


Analysis of covariance by the SAS GLM procedure.
Analysis of covariance (ANCOVA) is an important statistical procedure for the analysis of biomedical data; the procedure is used for the comparison of means between two or more groups of subjects exposed to contrasting stimulus with adjustment for confounding bias. Although ANCOVA is available in all the major statistical packages (e.g. SAS, SPSSX, BMDP), not all the important statistical aspects of ANCOVA are explicitly considered by these packages. This article expands the analysis of a numeric example included in the SAS GLM procedure to cover several crucial statistical aspects relevant to ANCOVA, and to highlight the meaning of the statistical results obtained.


Identification of Clinical Risk Factors Affecting Patient-Physician Communication.
Patient satisfaction is an important indicator of quality in health care and is linked to clinical outcomes, patient retention, and professional satisfaction. Patients admitted to the hospital from the emergency department may not understand their diagnosis, reason for admission or plan of care, which can adversely impact their hospital experience. We aim to identify risk factors that contribute to poor patient-physician communication and to assess the effects of raising awareness of these issues to hospital providers. From November 2020 to April 2021, patients admitted to the surgical floor were surveyed within 24 h of admission. Relevant data were extracted through retrospective chart review. Residents and attendings were debriefed regarding the improving communication. Surveys answered before and after the brief intervention were compared. One hundred thirty one patients who were admitted to the surgical floor were surveyed. Nineteen did not know their diagnoses (14.5%), 29 could not explain their diagnoses (22.1%), and 28 did not know their treatment plans (21.4%). A total of 38 (29.0%) patients answered "no" to at least one question. Trauma patients (P = 0.034), patients with pain score >4 at time of admission (P = 0.038), age >65 y (P = 0.047), and patients with >3 comorbidities were more likely to answer "no" to at least one of the questions. Postintervention, a 10% reduction in number of patients answering "no" was observed. Trauma patients, patients with poor pain control, the elderly, and those with multiple comorbidities are more likely to experience poor patient-physician communication. Raising awareness of the importance of this matter resulted in an improvement in communication.


Elevated growth velocity in children with Perthes' disease.
Sequential measurements of height and weight from diagnosis to maturity in 44 children with Perthes' disease are presented. Both boys and girls have an increased growth velocity after the age of 6 years. In boys diagnosed prior to the age of 6 years, the pubertal growth spurt occurs early but is not sustained. Girls have a delayed but rapid pubertal growth spurt. Abnormal growth patterns are further evidence for the concept of "the susceptible child" and increased growth velocity may contribute to trabecular failure and subsequent epiphyseal infarction.


New type of hip arthroplasty failure related to modular femoral components: breakage at the neck-stem junction.
Total hip replacements (THR) with modular femoral components (stem-neck interface) make it possible to adapt to extramedullary femoral parameters (anteversion, offset, and length) theoretically improving muscle function and stability. Nevertheless, adding a new interface has its disadvantages: reduced mechanical resistance, fretting corrosion and material fatigue fracture. We report the case of a femoral stem fracture of the female part of the component where the modular morse taper of the neck is inserted. An extended trochanteric osteotomy was necessary during revision surgery because the femoral stump could not be grasped for extraction, so that a long stem had to be used. In this case, the patient had the usual risk factors for modular neck failure: he was an active overweight male patient with a long varus neck. This report shows that the female part of the stem of a small femoral component may also be at increased failure risk and should be added to the list of risk factors. To our knowledge, this is the first reported case of this type of failure.


The isolectins of Helix pomatia. Separation by isoelectric focusing and preliminary characterization.
Helix pomatia lectin was fractionated into several (at least 12) components by isolectric focusing in PharmalyteTM. Eight of these were recovered from a preparative column experiment and shown to be essentially pure by analytical electrofocusing in polyacrylamide gel slabs. The lectin components had haemagglutinating activity against human group A erythrocytes and similar molecular weights of 80 000 as determined vidual components showed slight variations in composition. The components are considered to be isolectins. Isoelectric focusing of lectin samples prepared from single snails from two different biotopes showed isolectin patterns similar to that of pooled lectin. Gel filtration of the lectin and flat bed electrofocusing of isolated isolectins both in the presence of 6 M ura, indicated that the lectin molecules are formed by different combinations of a range subunits with similar molecular weight but with different isoelectric points.


Effect of Benzo(a)pyrene on the Expression of miR-483-3p in Hepatocyte Primary Culture and Rat Liver.
Here, we suggested that the epigenetic mechanism of benzo(a)pyrene (BP) action might be based on the aryl hydrocarbon receptor (AhR)-mediated transcription of the target genes, including miRNAs, that have the dioxin response element (DRE) in their promoters. The effect of BP on the expression of the oncogenic miR-483-3p, its host gene IGF2, and target gene IGF1 in primary hepatocytes and in the liver of Wistar female rats was investigated. The activation of AhR was confirmed using selective AhR inhibitor CH-223191 and by evaluating expression of the target CYP1A1 gene. The lack of coordination between the expression of miR-483-3p and its host gene IGF2 was revealed, which may be due to the presence of the binding site for the estrogen receptor alpha (ERα), which is a negative expression regulator. Our results confirm the existence of the AhR-mediated pathway in the regulation of expression of miR-483-3p, IGF1, and IGF2 under BP exposure, which is of considerable interest for understanding the epigenetic mechanisms of the carcinogenic effect of BP.


Biosynthesis of acid phosphatase of baker's yeast. Characterization of a protoplast-bound fraction containing precursors of the exo-enzyme.
1. Yeast protoplasts, secreting acid phosphatase (orthophosphoric-monoester phosphohydrolase (acid optimum) EC 126.96.36.199) contain a small amount of firmly bound enzyme, even after lysis (Van Rijn, H.J.M., Boer, P. and Steyn-Parvé, E.P. (1972) Biochim. Biophys. Acta 268, 431-441). The major part (70%) of this protoplast-bound acid phosphatase can be solubilized by nonionic detergents, such as Triton X-100. 2. The kinetics of radioactive amino acid incorporation in the solubilized and in the secreted enzyme has been estimated by pulse-chase labelling of secreting protoplasts, followed by fractionation and counting radioactivity in the enzyme band in polyacrylamide gels after electrophoresis at pH 5.0. A precursor-product relationship between the Triton X-100-extractable fraction of the protoplast-bound acid phosphatase and the secreted enzyme is apparent. 3. The solubilized acid phosphatase is essentially indistinguishable from the secreted enzyme with regard to a number of enzymatic properties and its stability towards pH and temperature. Both enzymes also behave alike on polyacrylamide-gel electrophoresis, producing a single acid phosphatase band with glycoprotein character and comparable mobility. 4. A striking difference is seen in isopycnic equilibrium sedimentation in CsCl: the secreted acid phosphatase is homogeneous, with a buoyant density of p equals 1.47 g/cm3, while the Triton X-100-extractable part of the protoplast-bound acid phosphatase is heterogeneous; besides heavier material a major component with buoyant density of p equals 1.37 g/cm3 is always visible.


[A clinical study on the effect of Yinxing Damo combined with betahistine hydrochloride injection on vertebral basilar artery ischemic vertigo].
To evaluate the therapeutic efficacy of Yinxing Damo (YXDM) combined with Betahistine Hydrochloride Injection (BHI) on vertebra basilar artery ischemic vertigo (VBIV). Ninety patients with VBIV were randomly divided into two groups; 45 patients (the treated group) were treated with YXDM and BHI intravenous dripping, once a day for 14 days. Another 45 patients (control group) were treated with Xueshuantong and BHI intravenous dripping, once daily for 14 days. The clinical syndromes and the index of the transcranial Doppler (TCD) and hemorheology were observed. The total effective rate was 100% in the treated group, which was better than that in the control group 90.5%, (P < 0.05). The indexes of TCD and hemorheology in the treated group were obviously improved after treatment, (P < 0.01). YXDM combined with BHT injection had better effect in treating patients with VBIV is an ideal drug for VBIV.


Reconstitution of a voltage and calcium dependent potassium channel from rat cerebellum.
Membrane vesicles from rat cerebellum were reconstituted into lipid bilayers. The activity of two different potassium channels was recorded: (1) a small conducting voltage dependent potassium channel insensitive to [Ca2+]i, (2) a calcium and voltage dependent potassium channel (KCa). KCa channels had a conductance of (302+/-15) pS (n=5) and were activated by [Ca2+]i and membrane depolarizations. They were blocked by tetraethylamonium (TEA) and charybdotoxin (CTX) but insensitive to noxiustoxin (NTX). Finally, we showed the blocking effect of Androctonus australis Hector (AaH) scorpion venom on KCa channels from rat cerebellum.


Open Skies in ASEAN.
The countries of Association of South-East Asian Nations (ASEAN) have agreed to the formation of open skies within the region. Member countries differ widely in terms of their GDP per capita, their size, aviation policies and the strength of their aviation industries. Granted these differences, several possibilities for facilitating the move are examined. These include taking an economic approach to aviation negotiations, liberalising within sub-regional groupings, a staged framework of liberalisation, and increasing the scope for low-cost carriers to compete, possibly through development of secondary markets. Moves will also necessitate attention being given to complementary issues, such as competition and subsidy policies and ownership.


Aesthetic reconstruction of the nasal tip using a folded composite graft from the ear.
Defects of the nasal tip, the alar, and the columella were treated with composite grafts from the postauricular area. The graft was folded into a three-dimensional shape, which provided a three-layered reconstruction of skin, cartilage and nasal lining. This procedure preserved the shape of the reconstruction for a longer time and yielded a good aesthetic result. Moreover, although this method was simple and was carried out in one stage, it left minimal morbidity of the donor site, and produced satisfying results.


Enhanced bioavailability of triprolidine from the transdermal TPX matrix system in rabbits.
The pharmacokinetics and bioavailability of triprolidine, antihistamines, were studied to determine the feasibility of enhanced transdemal delivery of triprolidine from the poly(4-methyl-1-pentene) (TPX) matrix system containing polyoxyethylene-2-oleyl ether in rabbits. The triprolidine-TPX matrix (50 mg/kg) was applied to abdominal skin of rabbits. Blood samples were collected via femoral artery for 36 h and the plasma concentrations of triprolidine were determined by HPLC. Pharmacokinetic parameters was calculated using the LAGRAN computer program. The area under the curve (AUC) was significantly higher in the enhancer group (4058 +/- 1420 ng/ml h) than that (1902 +/- 857 ng/ml h) in control group (P<0.05), showing about 235% increased bioavailability. The average Cmax was increased significantly in the enhancer group (216 +/- 44.3 ng/ml) compared with control group (130 +/- 25.8 ng/ml) (P<0.05). The mean Tmax was increased in the enhancer group (8.0 +/- 2.55 h) compared with the control (6.0 +/- 2.28 h) but was not significant. The relative bioavailability was 23.1% in the control group and 49.3% in the enhancer group compared to the oral route. As the triprolidine-TPX matrix containing polyoxyethylene-2-oleyl ether as an enhancer and tiethyl citrate as a plasticizer was administered to rabbits via the transdermal routes, the relative bioavailability increased by about 2.13-fold compared to the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The results of this study shows that triprolidine-TPX matrix could be developed as a transdermal delivery system providing consistent plasma concentration.


[Results of the treatment of pathologic fractures of long tubular bones].
The treatment of pathological bone fractures will be analysed by 53 patients of the Surgical Clinic of the University of Tübingen in view of fractures reason, operative providing and prognosis. The first aim consist in correction or preservation of live quality. Fractures nearly joints can be treated by endoprothetics. With the help of compound osteosynthesis most fractures can be stabilized. Conservative treatment only in final phase is legitimated.


[Breast cancer survivors: quality of life and prevailing diagnoses].
Knowledge of the Quality of Life (QoL) of surviving patients with breast cancer using an effective tool, and adapting it to nursing language using NANDA taxonomy, is essential to identify their needs and health problems. To evaluate the QoL of women diagnosed with breast cancer in 2004 (survivors). To identify the most common health problems, and adapting them to the NANDA taxonomy. A cross-sectional descriptive study was conducted using a QoL Survey (EORTC QLQ-C30 and BR23) in breast cancer survivors with the collection of demographic and clinical data (October-December 2009). Descriptive statistics (SPSS 18.0) were performed, as well as an analysis of the responses to questionnaire items, identifying defining characteristics, related factors and actual/potential diagnoses (NANDA taxonomy). The study included 140 participants. There was a significant effect on: Sexual Function (23.16 ± 25.85), Sexual Enjoyment (48.3 ± 29.15), Concern for the future (51.63 ± 32.32), insomnia (33.03 ± 33.91) and Concern for hair loss (32.67 ± 33.67). The most prevalent health problems were: inefficient sexual pattern (87.1%), body image disorder (80.7%), anxiety (41.5) and sexual dysfunction (31.7%). The relationship between these, the defining characteristics, the related factors and key questionnaire items for their identification are shown. The QoL of breast cancer survivors is affected in various fields. The EORTC scale can be used as a focused evaluation of QoL. Evidence is provided on the most prevalent diagnoses in survivors, being a first step towards standardisation of care. Research on nursing interventions aimed at improving the QOL of patients is necessary.


Mutational and immunochemical analysis of plasminogen activator inhibitor 1.
We have undertaken a structural and functional analysis of recombinant plasminogen activator inhibitor type 1 (PAI-1) produced in Escherichia coli using site-directed mutagenesis and immunochemistry. Expression of recombinant PAI-1 yielded an inhibitor that was functionally indistinguishable from PAI-1 made in human endothelial cells. Mutations in both the reactive center P1 and P1' residues (Arg-Met) and a putative secondary binding site for plasminogen activators on PAI-1 have been engineered to assess their functional effects. The inhibition of a panel of serine proteases, including plasminogen activators, trypsin, elastase, and thrombin, has been studied. Substitution of the P1 arginine residue with lysine or the P1' residue with either valine or serine had no detectable effect on the rate of inhibition of plasminogen activators. However, replacement of both P1 and P1' by Met-Ser produced a variant with no detectable plasminogen activator inhibitor activity. Mutations introduced into either Asp102 or Lys104 in the second site did not affect the rate of inhibition of plasminogen activators. Complementary immunochemical experiments using antibodies directed against the same two regions of the PAI-1 protein confirm that the reactive center is the primary determinant of inhibitory activity and that the putative second site is not a necessary functional region.


Design and construction of an accelerator-based boron neutron capture therapy (AB-BNCT) facility with multiple treatment rooms at the Southern Tohoku BNCT Research Center.
Installation of an accelerator-based boron neutron capture therapy (AB-BNCT) system was started in April 2014 at the Southern Tohoku BNCT Research Center (STBRC), and clinical trials began in January 2016. There are two treatment rooms, which have same specifications, and the beam quality equivalency was confirmed both rooms. Here, we describe the design and construction of the first hospital-based AB-BNCT facility in the world with multiple treatment rooms.


Adherence to inhaled corticosteroids and long-acting β2-agonists in asthma: A MASK-air study.
Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting β2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA. We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day. In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001). In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.


Textile dye removal in wastewater by peroxymonosulfate (PMS) activation on a zero-valent iron nanoparticle-modified ultrafiltration catalytic membrane (nZVI@PES).
The use of the nano zero-valent iron (nZVI) nanoparticle-based advanced oxidation systems in conjunction with an activator such as peroxymonosulfate (PMS) to generate hydroxyl and sulfate radicals for the degradation of organic pollutants has been extensively used in recent studies. In this study, a nZVI-modified polyethersulfone (PES) membrane (nZVI@PES) was produced successfully by attaching the nZVI catalytic nanoparticles on the surface of a commercial microporous polymeric membrane material using a simple and easy filter press coating method. The presence of nZVI nanoparticles on the nZVI@PES membrane was confirmed by XRD, SEM, and EDS analyses. The nZVI@PES membrane was applied in the dead-end filtration system in the presence of the PMS activator to treat the reactive black 5 (RB5) dye solution. The effect of catalyst loading, RB5 dye concentration, PMS dosage, and pH level on the nZVI@PES membrane/PMS system was investigated. Quenching experiments were carried out to identify the reactive species responsible, and reusability tests were conducted on the membrane. The highest decolorization efficiency (96.8%) was obtained at 20 mg/L RB5 dye solution, initial pH of 3, the nZVI loading of 5 mg/cm2, and the PMS dosage of 300 mg/L at the end of a reaction time of 30 min. The formation of HO•, [Formula: see text], [Formula: see text] and, 1O2 was confirmed by quenching experiments. The results indicate that the nZVI@PES membrane/PMS system could successfully treat wastewater contaminated with an organic dye.


Cumulative dairy cow genetic change from selection and crossbreeding over the last 2 decades in New Zealand closely aligns to model-based predictions published in 2000.
A deterministic model was developed in 1998 to evaluate the concurrent effects of selection and crossbreeding on the rate of genetic gain and increases in productivity of New Zealand dairy cattle over the ensuing 25-yr period. The predictions of today's breed composition of the national dairy herd and genetic trends for body weight and lactation yields of milk, fat, and protein are compared with today's actual values. Selection was assumed to use an index that included live weight and lactation yields of milk, fat, and protein. Mating strategies involving the Holstein-Friesian (F), Jersey (J), and Ayrshire (A) breeds were evaluated. Effects of heterosis and age were included to calculate phenotypic live weight and yields of milk, fat, and protein per cow. At the time the model was developed, New Zealand had an across-breed evaluation system, but only straightbred bulls were used after progeny testing based on records of straightbred and crossbred daughters. The model predicted that if crossbred cows and bulls could be considered as bull parents, faster rates of genetic gain may result because of increased selection intensities in the cow to breed bull selection pathway. This scenario transpired, and the best bulls and cows for farm profit were used regardless of breed. Under that mating strategy for the 2018 birthyear, the model predicted the national breed composition would be 11% F, 34% J, 52% F×J, and 2% A; the actual breed composition was 36% F, 9% J, 53% F×J, and 1% A. The model-predicted annual genetic gains would be 16.7 L of milk, 1.2 kg of fat, 1.5 kg of protein, and -0.7 kg of body weight; the realized annual improvements were 13.6 L of milk, 1.31 kg of fat, 1.17 kg of protein, and -0.36 kg of body weight. Predicted long-term responses to selection can closely mirror realized improvements, confirming the value of modeling to inform animal breeding decision-making.


Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy.
Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.


Bathing water profile in the coastal belt of the province of Pescara (Italy, Central Adriatic Sea).
The quality of bathing water is fundamental, not only from an environmental point of view but also due to the economic importance of tourism. This paper examines the water profile in the coastal belt of the province of Pescara (Italy, Central Adriatic Sea) with reference to the microbiological parameters Escherichia coli and intestinal enterococci required by Directive 2006/07 of European Commission. The water quality of 15 coastal beaches was surveyed; data were produced from monitoring and controls made available by the Abruzzo Regional Environmental Prevention and Protection Agency (ARTA) and extracted and elaborated for the period of interest (2010-2013). Statistical analysis was used to confirm the aspects deduced from mean values of monitoring and control data for each stretch. The data highlight critical situations in various parts of the coast; these problems can be attributed to river pollution, mainly due to the malfunctioning of the treatment plants for urban wastewater.


[The Austrian tonsil study 2010--part 1: statistical overview].
Tonsillectomy (TE), tonsillotomy (TO) and adenoidectomy (AE) are surgeries performed routinely by otorhinolaryngologists. There were 5 cases of fatal postoperative bleeding in Austria during the years 2006 and 2007, all in children under 6 years of age. The intensive discussion following these sad events resulted in a Consensus Paper of the Austrian Society of ORL, H&NS with the Austrian Society of Pediatrics with modified recommendations towards indications and surgical techniques in different age groups; in addition, the prospective study presented here was initiated. In Austria for the first time a full census could be performed assessing all TE, TO and AE with standardized definitions. Within the study period of 9 months' from October 1, 2009, to June 30, 2010, data on patients' characteristics, indication for surgery, surgical technique and postoperative haemorrhage were prospectively collected. Postoperative haemorrhage was defined as any bleeding after extubation regardless of whether or not a surgical intervention was required. Postoperative bleeding events were categorised into 7 grades depending on severity. More than one million data of 9,405 patients from 32 ENT-departments in Austria were collected and analysed. One third were children younger than 6 years (n=3,474; 37%) and one third were adults (n=3,507, 37%). A TE ±AE was performed in 48.8% (n=4,594), an AE in 37.1% (n=3,492) and a TO in 14.0% (n=1, 319). For the indication "recurrent tonsillitis and tonsilar hypertrophy" 70% of children had a TO but 95% of adults had a TE (p<0.001). Adults with OSAS had a TE whereas in children aged younger than 6 with the same indication a TO was preferably performed in 90% (p<0.001). For TO the Colorado-needle and the Coblation technique were most commonly used. The Adenotome by La Force and the Adenoid curette by Beckmann, with or without endoscopic control, were most frequently used for AE. For the first time a prospective full survey could be performed in one country assessing all tonsil and adenoid surgeries along standardized criteria. The study gives an overview about the types of surgery, the indications, the operation techniques and the frequency of postoperative haemorrhage. The latter, because of its clinical importance, is dealt with and described in detail in the second part of this publication.


Single center evaluation of outcomes of modular dual mobility liners during revision total hip arthroplasty: A five-year follow-up.
Revision total hip arthroplasty (rTHA) is at increased risk for postoperative instability when compared to primary cases, which has been mitigated to some extent with the introduction of dual mobility (DM) reconstructions. These constructs were designed to lower dislocation rates and to improve impingement-free range of motion. As a follow-up to our prior institutional study, we expanded on a cohort of DM reconstructions compared to non-DM constructs. We examined a modular dual mobility system in rTHA to measure loosening of the acetabular component, as well as revision and dislocation rates in comparison to an historical cohort of single articulation prostheses.Materials/Methods: This retrospective cohort study from a single center included 254 patients who underwent rTHA with a dual mobility liner by three fellowship-trained surgeons between January 1, 2014 and December 1, 2019. This was a follow-up to an historical cohort of revisions performed with a single articulation prosthesis (n = 120) from the same surgeons performed between January 1, 2011 and December 23, 2013. The inclusion criteria included consecutively performed rTHAs that had a minimum follow-up of 2 years. We excluded patients who had femoral revisions and head/liner revisions only. The average follow-up in the dual mobility cohort and the single articulation cohort was 5 years (range, 2-10 years) and 2.5 years (range, 1.5-4.3 years), respectively. The primary outcomes were dislocation, aseptic loosening, and re-revision rates. Secondary outcomes were radiographic analyses of cup migration and osteolysis. There were 4 out of 256 (1.6%) dislocations from the dual mobility cohort compared to 7 out of 120 (5.8%), P < 0.001 from the single articulation cohort. The rates of aseptic loosening were 3.2% (8 out of 254) and 4.2% (5 out of 120), P = 0.124, respectively, between the cohorts. The re-revision rate was 5.9% for the DM liners and 8.3% in the control cohort, P = 0.38. Radiographic analyses revealed no cup migration and osteolysis in any of the patients that had no dislocations. The dual mobility articulations in rTHA demonstrated improved results in terms of lower dislocations rates when compared to a single articulation prostheses. Our center uses these articulations for revisions and surgeons should consider the use of these bearings when performing rTHA.


The innate pulmonary granuloma: characterization and demonstration of dendritic cell recruitment and function.
Granulomas are innate sequestration responses that can be modified by superimposed acquired immune mechanisms. The present study examined the innate stage of pulmonary granuloma responses to bead-immobilized Th1- and Th2-inducing pathogen antigens (Ags), Mycobacteria bovis purified protein derivative (PPD) and Schistosoma mansoni soluble egg Ags (SEA). Compared to a nonpathogen Ag, PPD and SEA bead elicited larger lesions with the former showing accelerated inflammation. Temporal analyses of cytokine and chemokine transcripts showed all Ag beads induced tumor necrosis factor-alpha mRNA but indicated biased interleukin (IL)-1, IL-6, and IL-12 expression with PPD challenge. All beads elicited comparable levels of CXCL9, CXL10, CCL2, CCL17, and CCL22 mRNA, but PPD beads caused biased CXCL2 CXCL5, CCL3, and CCL4 expression whereas both pathogen Ags induced CCL7. Immunohistochemical, electron microscopic, and flow cytometric analyses showed that Ag beads mobilized CD11c+ dendritic cells (DCs) of comparable maturation. Transfer of DCs from PPD Ag-challenged lungs conferred a Th1 anamnestic cytokine response in recipients. Surprisingly, transfer of DCs from the helminth SEA-challenged lungs did not confer the expected Th2 response, but instead rendered recipients incapable of Ag-elicited IL-4 production. These results provide in vivo evidence that lung DCs recruited under inflammatory conditions favor Th1 responses and alternative mechanisms are required for Th2 commitment.


Defective protein degradation in genetic disorders.
Understanding the molecular mechanisms that underlie different human pathologies is necessary to develop novel therapeutic strategies. An emerging mechanism of pathogenesis in many genetic disorders is the dysregulation of protein degradation, which leads to the accumulation of proteins that are responsible for the disease phenotype. Among the different cellular pathways that regulate active proteolysis, the Cullin RING E3 ligases represent an important group of sophisticated enzymatic complexes that mediate substrate ubiquitination through the interaction with specific adaptors. However, pathogenic variants in these adaptors affect the physiological ubiquitination of their substrates. This review discusses our current understanding of this emerging field.


Programmed Cell Death-1/Ligand-1 PET Imaging: A Novel Tool to Optimize Immunotherapy?
Clinical indications for immune checkpoint inhibitor (ICI) therapy are rapidly expanding for various stages of several solid tumors. The success of ICIs results from a complex interplay between cancer cells and their immune microenvironment. PD-1/PD-L1 PET imaging enables to study of these interactions in the tumor microenvironment in a clinical setting. These noninvasive, sensitive and quantitative tools may play an important role in optimizing ICI efficacy.


Economic evaluation and comparison of migration paths for the smart grid using two case studies.
Today, European utility companies are facing the conversion of their power grids from a previously centrally controlled supply to a then decentralized supply. These changes are necessary to achieve the climate targets. In order to create a decentralized power grid, the integration of modern information and communication technologies (ICT) and other hardware is necessary. On the one hand, the utilities must know which paths they can take to make their power grid intelligent, but on the other hand it is also crucial to know the costs involved. In this contribution we outline a possible model for technological migration paths with a corresponding economic analysis based on German and European case studies.


Nuclear heterogeneity in conidial populations of Aspergillus flavus.
Aspergillus flavus is a major producer of aflatoxin and an opportunistic pathogen for a wide range of hosts. Understanding genotypic and phenotypic variation within strains of A. flavus is important for controlling disease and reducing aflatoxin contamination. A. flavus is multinucleate and predominantly haploid (n) and homokaryotic. Although cryptic heterokaryosis may occur in nature, it is unclear how nuclei in A. flavus influence genetic heterogeneity and if nuclear condition plays a role in fungal ecology. A. flavus mainly reproduces asexually by producing conidia. In order to observe whether conidia are homokaryotic or heterokaryotic, we labeled nuclei of A. flavus using two different nuclear localized fluorescent reporters. The reporter constructs (pYH2A and pCH2B), encode histones HH2A and HH2B fused at the C terminus with either yellow (EYFP) or cyan (ECFP) fluorescent proteins, respectively. The constructs were transformed into the double auxotrophic strain AFC-1 (-pyrG, -argD) to generate a strain containing each reporter construct. By taking advantage of the nutritional requirement for each strain, we were able to generate fusants between FR36 (-argD) expressing yellow fluorescence, and FR46 (-pyr4) expressing cyan fluorescence. Conidia from fusants between FR36 and FR46 showed three types of fluorescence: only EYFP, only ECFP or both EYFP+ECFP. Conidia containing nuclei expressing EYFP+ECFP were separated by Fluorescence-Activated Cell sorting (FACS) and were found to contain both yellow and cyan fluorescent markers in the same nucleus. Further characterization of conidia having only one nucleus but expressing both EYFP+ECFP fluorescence were found to be diploid (2n). Our findings suggest that A. flavus maintains nuclear heterogeneity in conidial populations.


The emerging roles of HDACs and their therapeutic implications in cancer.
Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and cancers. Acetylation is one of the most common post-translational modifications of proteins, and the acetylation levels are controlled by two mutually antagonistic enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HATs loosen the chromatin structure by neutralizing the positive charge of lysine residues of histones; whereas HDACs deacetylate certain histones, thus inhibiting gene transcription. Compared with HATs, HDACs have been more intensively studied, particularly regarding their clinical significance. HDACs extensively participate in the regulation of proliferation, migration, angiogenesis, immune escape, and therapeutic resistance of cancer cells, thus emerging as critical targets for clinical cancer therapy. Compared to HATs, inhibitors of HDAC have been clinically used for cancer treatment. Here, we enumerate and integratethe mechanisms of HDAC family members in tumorigenesis and cancer progression, and address the new and exciting therapeutic implications of single or combined HDAC inhibitor (HDACi) treatment.


The anorectal sphincter after rectal pull-through surgery for anorectal anomalies: MRI evaluation.
The puborectalis muscle sling was evaluated with MRI in 10 pediatric patients who had rectal pull-through surgery for anorectal anomalies. MRI (1.5T) demonstrated the puborectalis muscle equally or better than CT in 5 patients who had both CT and MRI. The amount of puborectalis muscle mass and the location of the pulled-through intestine in relation to the puborectalis sling was well shown with MRI. Our study suggests that MRI can be reliably substituted for CT in the majority of these patients, to assist in planning further surgery for relief of persistent postoperative fecal incontinence.


COVID-19 vaccine effectiveness against omicron (B.1.1.529) variant infection and hospitalisation in patients taking immunosuppressive medications: a retrospective cohort study.
There is a scarcity of research regarding the effectiveness of the mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines in patients taking immunosuppressant medications, and no data are published to date pertaining to their effectiveness against omicron (B.1.1.529) variant SARS-CoV-2 infection and hospitalisation. We aimed to assess the relationship between immunosuppressive medications, mRNA vaccination, omicron infection, and severe COVID-19 outcomes (ie, hospitalisation, ICU admission, death). We did a retrospective cohort study and included vaccinated and unvaccinated people aged 18 years or older in the Michigan Medicine health-care system, USA, during the omicron-dominant period of the pandemic (Dec 16, 2021-March 4, 2022). We collected data from electronic health records (demographics, diagnoses, medications) combined with immunisation data from the Michigan State Registry to determine vaccination status, and we collected COVID-19-related hospitalisation data by chart review. We used a Cox proportional hazards model based on calendar time to assess the effectiveness of the mRNA-1273 and BNT162b2 vaccines in people taking immunosuppressive medications (conventional synthetic disease-modifying antirheumatic drugs [DMARDs], biologic DMARDs, or glucocorticoids within the past 3 months), while controlling for participant characteristics. Using the same model, we assessed the effect of different classes of medication such as immunosuppressive DMARDs, immunomodulatory DMARDs, and glucocorticoids on SARS-CoV-2 infection and hospitalisation due to COVID-19. All analyses were done using complete cases after removing participants with missing covariates. 209 492 people were identified in Michigan Medicine, including 165 913 who were vaccinated and 43 579 who were unvaccinated. 41 078 people were excluded because they were younger than 18 years, partially vaccinated, had received a vaccine other than the two vaccines studied, or had incomplete covariate data. 168 414 people were included in the analysis; 97 935 (58%) were women, 70 479 (42%) were men, and 129 816 (77%) were White. 5609 (3%) people were taking immunosuppressive medications. In patients receiving immunosuppressants, three doses of BNT162b2 had a vaccine effectiveness of 50% (95% CI 31-64; p<0·0001) and three doses of mRNA-1273 had a vaccine effectiveness of 60% (42-73; p<0·0001) against SARS-CoV-2 infection. Three doses of either vaccine had an effectiveness of 87% (95% CI 73-93; p<0·0001) against hospitalisation due to COVID-19. Receipt of immunosuppressive DMARDs (hazard ratio 2·32, 95% CI 1·23-4·38; p=0·0097) or glucocorticoids (2·93, 1·77-4·86; p<0·0001) and a history of organ or bone marrow transplantation (3·52, 2·01-6·16; p<0·0001) were associated with increased risk of hospitalisation due to COVID-19 compared with those who had not received immunosuppressive medications or transplant. People taking immunosuppressive DMARDs or glucocorticoids are at substantially higher risk of hospitalisation due to COVID-19 than the general population. However, the mRNA-1273 and BNT162b2 vaccines remain effective within this group, and it is important that patients taking these medications remain up to date with vaccinations to mitigate their risk. National Institute of Allergy and Infectious Diseases, National Institutes of Health.


Common features of patients with autoimmune atrophic gastritis.
Autoimmune atrophic gastritis (AIG) is characterized by immune-mediated chronic inflammation of the gastric body and fundus, leading to hypo-achlorhydria and vitamin B12 deficiency. We analyzed the clinical features of AIG and sought to identify factors that might be used in diagnosis. We collected and analyzed clinical data from 99 consecutive patients (age, 59 ± 17 y) who were diagnosed with AIG, based on histologic factors and the presence of autoantibodies against gastric parietal cells. Clinical factors that led to a diagnosis of AIG included hematologic findings related to vitamin B12 deficiency (n = 37), incidental histologic evidence in gastric biopsy specimens (n = 34), immune disorders (n = 18; 9 were celiac disease), neurologic symptoms (n = 6), and a family history of AIG (n = 4). Based on an analysis of 99 consecutive patients with AIG, this disorder is not solely a condition of the elderly. Other features to look for in making a diagnosis of AIG include vitamin B12 deficiency, histologic factors, and immune disorders.


Odor-elicited activity monitored simultaneously from 124 regions of the salamander olfactory bulb using a voltage-sensitive dye.
In response to controlled, odor pulse stimulation of the olfactory receptor mucosa, large fluorescence signals were recorded simultaneously from 124 contiguous anatomical regions of the salamander olfactory bulb using the potentiometric probe RH 414. The amplitudes and waveforms of the signals varied systematically across the bulbar surface in apparent correspondence with the laminae of the bulbar neurons. Qualitatively similar results were obtained using both intact and decorporate preparations, although fluorescence signals obtained from intact animals were distorted by optical noise generated by mechanical disturbances related to the functioning cardiovascular system. These results indicate that multiple site optical recording can be used to obtain information about spatio-temporal patterning of bulbar electrical activity evoked by physiological odor stimulation of the receptor mucosa. This is the first demonstration that activity elicited by a single, one second odor stimulus at physiological concentration and duration can be measured across many elements in the olfactory bulb. Information provided by this approach, in combination with complementary data derived from 2-deoxyglucose and single unit studies, may yield a better understanding of how the vertebrate central nervous system extracts quality and concentration information from olfactory afferent input.


The prevention and treatment of radiotherapy - induced xerostomia.
Efforts to reduce the severity of postradiotherapy xerostomia include the use of salivary substitutes to gain symptomatic relief, salivary gland stimulants, agents delivered to protect the glands during radiotherapy (RT), and physical means to partially spare the major salivary glands from RT while adequately irradiating tumor targets. These means include advanced RT treatment planning and salivary tissue transfer to nonirradiated areas. The relative potential gain from each of these strategies is discussed in this article. The combination of partial salivary gland sparing and radiation protectors/stimulants may provide additive or synergistic gains in reducing the severity of xerostomia.


A second-generation ELISA (STRATIFY JCV™ DxSelect™) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification.
JC virus (JCV) infection is a prerequisite for development of progressive multifocal leukoencephalopathy (PML). The development and validation of a two-step enzyme-linked immunosorbent assay (ELISA) that detects JCV antibodies in human serum or plasma and its clinical utility for stratification of PML risk have been described. To develop a second-generation JCV antibody ELISA kit with improved assay performance characteristics. The assay design was optimized by pre-coating the JC virus-like particles (VLP) on microtiter plates. Assay cut-points were statistically established using sera from >1300 multiple sclerosis patients from natalizumab clinical studies. The assay was analytically validated and then used to determine the presence of JCV antibodies in both treatment-naïve and natalizumab-treated MS patients, as well as in natalizumab-treated PML patients. An improved assay for detection of JCV antibodies in human serum and plasma was developed. Key enhancements included improved delineation and reproducibility of low JCV antibody responses and assay ease of use. The assay was validated, demonstrating good agreement with the original two-step JCV antibody ELISA, and similar seroprevalence of 50%-60%. Samples from 63 natalizumab-treated PML patients collected 6-180 months prior to PML diagnosis tested JCV antibody positive. One patient tested JCV antibody negative 15 months prior to PML diagnosis but JCV antibody positive 2 months prior to PML diagnosis. The validated second-generation JCV antibody ELISA offers improved assay design as a kit and enhanced performance characteristics that advance routine clinical use of the assay as a PML risk stratification tool.


Effects of NMDA receptor antagonists on nociceptive responses in vivo: comparison of antagonists acting at the glycine site with uncompetitive antagonists.
We have shown that members of a new series of tricyclic pyridophthalazine diones, defined as glycineB site NMDA antagonists in vitro, are selective and systemically active NMDA antagonists in vivo. In electrophysiological tests in alpha-chloralose anaesthetised rats, these compounds reduced nociceptive reflex responses. In conscious rats they displayed analgesic properties. These glycineB antagonists were compared electrophysiologically with several uncompetitive NMDA channel blockers. The degree of voltage dependence previously reported in vitro related to the effectiveness of the agents against different amplitude nociceptive responses of spinal cord neurones in vivo.


Distribution of dietary trans-octadecenoate among acyl-CoA and other lipid fractions of rat liver and heart.
Groups of rats were fed diets containing 10% of either corn oil, partially hydrogenated soybean oil, or a mixture of the two. The partially hydrogenated oil contained a high level of trans-octadecenoate and a low level of linoleate, and all diets were adjusted to contain similar levels of cis-octadecenoate. The fatty acid compositions of five tissue lipid fractions from liver and heart (non-esterified fatty acids, acyl-CoA, diacylglycerols, triacylglycerols and phospholipids) were analyzed to measure the effect of the dietary supply on the accumulation of trans-octadecenoates and other fatty acids at different steps of glycerolipid synthesis. Although trans-octadecenoate was increased in all of the lipid fractions when the dietary supply was increased, the accumulation did not exceed 15% of the acyl chains in any of the lipid pools even when the dietary trans acid accounted for 46% of the fatty acids supplied in the diet. The trans-octadecenoate accumulated in a similar manner in the lipids of both liver and heart, and the amounts found in the acyl-CoA esters of both tissues were relatively low compared to the diet. A high dietary supply of trans-octadecenoate appeared to diminish the relative content of stearate in the acyl-CoA and phospholipid fractions. The level of cis-octadecenoate maintained in tissue phospholipids was similar to that in the acyl-CoA fractions, whereas the trans-octadecenoate content in phospholipids more closely resembled that in the diacylglycerols. Normal proportions of arachidonate were maintained in the tissue phospholipids during high intake of trans acids, even though lower levels were observed in the acyl-CoA and diacylglycerols of liver.


Drug consumption of suspected drug-influenced drivers in Hungary (2016-2018).
The hazard caused by driving under the influence of drugs (DUID) is determined by the time of consumption, dose and biological effects of a substance, as well as by synergistic drug interactions after multi-drug use. The aim of this work was to investigate the prevalence and pattern of psychoactive substance use of suspected DUID drivers and to present the advantages and disadvantages of the system currently used for determination of impairment in Hungary. Blood and urine samples, collected between 2016 and 2018, were taken from 2369 drivers with a positivity rate of 95% for at least one substance. Classical illicit drugs were detected in 76-87%, prescription medications in 9-15%, stimulant New Psychoactive Substances (sNPS) in 3-8%, and synthetic cannabinoids (SCs) in 20-22% of the positive samples. The most frequent substances according to substance groups were: classical illicit drugs: cannabis (n = 1240), amphetamine and methamphetamine (AM/MA) (n = 753), MDMA (n = 196), and cocaine (n = 180), medicines: alprazolam (n = 188) and clonazepam (n = 83), sNPS: N-ethyl-hexedrone (n = 115), SCs: 5 F-MDMB-PINACA (n = 267), AMB-FUBINACA (n = 92) and ADB-FUBINACA (n = 90). The median age of classical illicit drugs users was 29 years, prescription medicine users were 33 years old, sNPS users were 28 years, and SC users were 26 years old. Compared to the previous two years, we found pronounced changes in the ratio of sNPS (14% decrease) and SC users (10% increase), and in the pattern of NPS consumption. The ratio of multi-drug use varied between 38% and 50%. 69% of drivers tested positive were deemed impaired. Impairment was determined according to impairment limits (80-82%), multi-drug use (12-13%), and the result of medical investigation when a single active substance with no set impairment limit was detected in the blood (6-8%). The results of medical investigations may be uncertain due to the long time delay between arrest and clinical examination and to the structure of medical investigations created for determination of alcoholic impairment. In conclusion, a revision of the current medical investigation protocol is warranted to standardize clinical symptom scores that better correlate with driving impairment.


Separation of monosaccharides by hydrophilic interaction chromatography with evaporative light scattering detection.
Hydrophilic interaction liquid chromatography (HILIC) was used to separate monosaccharides that are common in N-linked oligosaccharides in glycoproteins and other compounds. A TSKgel Amide-80 column was eluted with 82% acetonitrile, in 5 mM ammonium formate (pH 5.5). Column temperature was 60 degrees C and evaporative light scattering was used for detection (ELSD). With this method, L-fucose, D-galactose, D-mannose, N-acetyl-D-glucosamine, N-acetylneuraminic acid, and D-glucuronic acid were separated, with detection limits of 0.3-0.5 microg for each monosaccharide, and intermediate precisions were 3-6% RSD (n=6).


Diagnostic performance of radiomics model for preoperative risk categorization in thymic epithelial tumors: a systematic review and meta-analysis.
Incidental thymus region masses during thoracic examinations are not uncommon. The clinician's decision-making for treatment largely depends on imaging findings. Due to the lack of specific indicators, it may be of great value to explore the role of radiomics in risk categorization of the thymic epithelial tumors (TETs). Four databases (PubMed, Web of Science, EMBASE and the Cochrane Library) were screened to identify eligible articles reporting radiomics models of diagnostic performance for risk categorization in TETs patients. The quality assessment of diagnostic accuracy studies 2 (QUADAS-2) and radiomics quality score (RQS) were used for methodological quality assessment. The pooled area under the receiver operating characteristic curve (AUC), sensitivity and specificity with their 95% confidence intervals were calculated. A total of 2134 patients in 13 studies were included in this meta-analysis. The pooled AUC of 11 studies reporting high/low-risk histologic subtypes was 0.855 (95% CI, 0.817-0.893), while the pooled AUC of 4 studies differentiating stage classification was 0.826 (95% CI, 0.817-0.893). Meta-regression revealed no source of significant heterogeneity. Subgroup analysis demonstrated that the best diagnostic imaging was contrast enhanced computer tomography (CECT) with largest pooled AUC (0.873, 95% CI 0.832-0.914). Publication bias was found to be no significance by Deeks' funnel plot. This present study shows promise for preoperative selection of high-risk TETs patients based on radiomics signatures with current available evidence. However, methodological quality in further studies still needs to be improved for feasibility confirmation and clinical application of radiomics-based models in predicting risk categorization of the thymic epithelial tumors.


Effectiveness of everolimus for sporadic renal angiomyolipoma with inferior vena cava thrombus: A case report.
Sporadic Renal Angiomyolipoma (AML) is commonly managed through transcatheter arterial embolization (TAE) or surgical intervention. In this report, we present a remarkable case of tumor regression from Novick Classification level 2 to level 1 in a 54-year-old male with sporadic renal AML and inferior vena cava (IVC) involvement, treated with the administration of everolimus. Subsequently, laparoscopic nephrectomy without cavectomy was performed. Notably, the patient did not present with tuberous sclerosis complex (TSC). Our findings highlight the potential of everolimus in the treatment of sporadic AML, even in cases unrelated to TSC, offering a viable alternative to invasive therapeutic approaches.


Standardization of specimen preparation, staining, and sampling methods improves automated sperm-head morphometry analysis.
To evaluate the accuracy and performance of the CellForm-Human automated sperm morphometry instrument (Motion Analysis Corp., Santa Rosa, CA) using different specimen preparation, staining, and analysis techniques. Clinical and research andrology and in vitro fertilization laboratories. Individuals who were undergoing semen evaluation and infertility work-up. The percentage of normal sperm detected by CellForm-Human was not different for washed specimens compared with nonwashed controls. Washing and resuspension to a standard concentration in medium significantly increased spermatozoan density and homogeneity on the slide. Comparison of digitization errors and morphometric measures of sperm stained by the Papanicolaou (PAP) method, the hematoxylin portion of the PAP method, and a new method developed by us, GZIN (pronounced Gee-ZIN), showed that GZIN produced larger measures for length, width, area, and perimeter, but not for width/length, and also produced less variability for most measures than PAP or hematoxylin. The number of digitization errors was significantly less for GZIN than for PAP. Visual inspection revealed that GZIN produced a more consistent stain over the entire sperm head than hematoxylin. The number of sperm analyzed affected the percentage of normal sperm detected. The % normal stabilized only after at least 200 sperm had been analyzed for each man. Technical variability arising from semen preparation and slide staining methods can be reduced when specimens are washed and resuspended to a standard concentration before smearing. At least 200 sperm should be analyzed to obtain a stable estimate of the percentage of normal sperm. More sperm should be analyzed if the % normal is < 50%. Morphometric measurements are more accurate and precise when sperm are stained with GZIN than when stained with PAP or hematoxylin.


[Scanner in cardiac and vascular pathology].
Computerized tomography (CT) has become a routine examination, but it is not well suited to the study of vascular and cardiac pathology. However, CT scans are very useful in the diagnosis and monitoring of aortic aneurysms and dissections, in the postoperative follow-up of surgical cardiac patients and in some cardiac pathologies, such as thrombosis or tumors.


Characterization of epitopes on a 32 kDa merozoite surface protein of Theileria sergenti.
Epitopes on a 32 kDa protein, which is an immunodominant major surface protein of Theileria sergenti, recognized by anti-merozoite monoclonal antibodies were characterized. The results of a competitive binding assay between monoclonal antibodies indicated that there were at least three epitopes in this protein. The presence of repeated epitopes was suggested by using two-site enzyme-linked immunosorbent assay. The protein was partitioned into the detergent phase of Triton X-114 extracts, indicating that the 32 kDa protein is an integral membrane protein. Periodate treatment of 32 kDa protein implies that one epitope of the epitopes recognized by monoclonal antibody has a carbohydrate moiety.


Ovarian mixed-epithelial papillary cystadenomas of borderline malignancy of mullerian type. A clinicopathologic analysis.
Borderline tumors with papillae that are architecturally similar to those of serous tumors but with a lining of more than one mullerian cell type have not been well characterized in in the literature. We have studied 36 such tumors. The patients averaged 35 years of age. Twenty-two percent of the tumors were bilateral; all were confined to the ovaries as confirmed at operation. Fifty-three percent were associated with endometriosis. Follow-up information was available on 34 patients for a mean interval of 4.8 years. A tumor developed in the contralateral ovary in one patient 2 years after unilateral salpingo-oophorectomy. Three patients had pelvic recurrences between 7 months and 3 years, but all of them were successfully treated and none have died. These tumors differ clinically and pathologically from intestinal-type mucinous borderline tumors, but they have many similarities with mullerian mucinous borderline tumors and, to a lesser extent, with serous borderline tumors.


Surgical management of parastomal hernia following radical cystectomy and ileal conduit: A french multi-institutional experience.
Parastomal incisional hernia (PH) is a frequent complication following the creation of an ileal conduit (IC), and it can be a significant detriment to quality of life. The aim of this study was to evaluate outcomes of PH repair following IC for urinary diversion. A multicenter retrospective study was conducted of 6 academic hospitals in France. The study's population included patients who underwent surgical treatment for parastomal hernia following IC creation from 2013 to 2021. Fifty-one patients were included in the study. Median follow up was 15.3 months. Eighteen patients presented with a recurrence (35%), with a median time to recurrence of 11.1 months. The vast majority of PH repair was performed through an open approach (88%). With regard to technique, Keyhole was the most reported technique (46%) followed by Sugarbaker (22%) and suture only (20%). The Keyhole technique was associated with a higher risk of recurrence compared to the Sugarbaker technique (52% vs 10%, p = 0.046). Overall, there was a 7.8% rate of major complications without a statistical difference between PH repair techniques for major complications. Surgical treatment of parastomal hernia following IC was associated with a high risk of recurrence. Novel surgical approaches to PH repair should be considered.


Biodegradation of the Herbicide 2,4-Dichlorophenoxyacetic Acid by a New Isolated Strain of Achromobacter sp. LZ35.
In this study, a bacterial strain of Achromobacter sp. LZ35, which was capable of utilizing 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxy acetic acid (MCPA) as the sole sources of carbon and energy for growth, was isolated from the soil in a disused pesticide factory in Suzhou, China. The optimal 2,4-D degradation by strain LZ35 occurred at 30 °C and pH 8.0 when the initial 2,4-D concentration was 200 mg L-1. Strain LZ35 harbored the conserved 2,4-D/alpha-ketoglutarate dioxygenase (96%) and 2,4-dichlorophenol hydroxylase (99%), and catabolized 2,4-D via the intermediate 2,4-dichlorophenol. The inoculation of 7.8 × 106 CFU g-1 soil of strain LZ35 cells to 2,4-D-contaminated soil could efficiently remove over 75 and 90% of 100 and 50 mg L-1 2,4-D in 12 days and significantly released the phytotoxicity of maize caused by the 2,4-D residue. This is the first report of an Achromobacter sp. strain that was capable of mineralizing both 2,4-D and MCPA. This study provides us a promising candidate for its application in the bioremediation of 2,4-D- or MCPA-contaminated sites.


Sublethal necroptosis signaling promotes inflammation and liver cancer.
It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.


The expression of telomeric proteins and their probable regulation of telomerase during the differentiation of all-trans-retinoic acid-responsive and -resistant acute promyelocytic leukemia cells.
Telomerase activity has been linked to retinoid induction of tumor cell differentiation, and the patterns of telomerase expression are different in the 2 pathways of acute promyelocytic leukemia (APL) cell differentiation: the retinoic acid receptor 3 (RAR3)-dependent and the retinoic X receptor 3 (RXR3)-dependent pathways. Still, whether telomeric proteins respond to retinoid treatment is not clear. If they do, how they would respond and how they would interfere in telomerase regulation during differentiation are also unclear. Using all-trans-retinoic acid (ATRA)-sensitive and -resistant APL cell lines NB4, NB4-R1, and NB4-R2, we analyzed a panel of telomeric proteins, including TRF1, PINX1, TANK1, and TANK2, at the messenger RNA (mRNA) and protein expression levels during the differentiation of these cell lines in the 2 pathways. Our analyses showed that both mRNA and protein expression of TRF1 remained stable during NB4 and NB4-R1 cell differentiation but slightly increased in NB4-R2 cells, suggesting that TRF1 may have different functions in the RAR3- and RXR3-dependent pathways. The stable expression of TRF1 may be because telomere length remains unchanged. Pinx1 mRNA expression was tightly correlated with telomerase reverse transcriptase (hTERT) mRNA expression during differentiation. Variation in Pinx1 expression may be a reaction induced by hTERT expression variation. TANK1 mRNA expression and TANK1 protein levels were both down-regulated in all 3 APL cell lines at a later period of differentiation, suggesting that TANK1 may positively regulate telomerase activity and that both RAR3- and RXR3-dependent pathways may exert this regulation.TANK2 expression levels remained stable in all 3 APL cell lines during differentiation, showing that TANK2 may have little effect on telomerase. Thus, our studies provide an outline of the dynamics of telomeric protein expression and the probable regulatory effects of these proteins on telomerase during the differentiation of ATRA-responsive and -resistant APL cells.


Attitudes towards highly active antiretroviral therapy are associated with sexual risk taking among HIV-infected and uninfected homosexual men.
To determine whether attitudes towards highly active antiretroviral therapy (HAART) are associated with unprotected anal sex among sexually active homosexual men. Cross-sectional study nested within an ongoing prospective cohort study. Multicenter AIDS Cohort Study, from April through September 1999. Five-hundred and forty-seven homosexual men reporting anal sex (218 HIV-negative and 329 HIV-positive) during study interviews in 1999, including a 20-item validated scale on attitudes toward HAART and HIV risk behaviors (e.g., 'Because of HAART, I am less concerned about becoming HIV-infected or infecting someone'), and safer sex fatigue (e.g., 'I am tired of always having safer sex'). Self-reported unprotected receptive anal sex (RAS) and insertive anal sex (IAS) in the prior 6 months. More than 50% of HIV-negative and HIV-positive men who reported having anal sex also reported recent unprotected RAS and/or IAS. HIV-negative men who most agreed that HAART reduced concern about becoming infected were more likely to report unprotected RAS compared to other HIV-negative men [adjusted odds ratio (AOR), 3.31; 95% confidence interval (CI), 1.27-8.62]. Moreover, HIV-positive men with greatest reduced concern due to HAART or safer sex fatigue were more likely to report unprotected IAS (AOR, 6.05; 95% CI, 2.24-16.63 and AOR, 4.57; 95% CI, 1.70-12.24, respectively) compared to other HIV-positive men. Among sexually active homosexual men, lessened concern about HIV transmission due to HAART was strongly associated with sexual risk taking, as was safer sex fatigue among HIV-positive men. Prevention programs should take into account underlying attitudes for unprotected sex in the era of HAART among both HIV-infected and uninfected men.


Male-female differences in the risk of tuberculosis in dialysis patients.
To define any gender-related differences in the prevalence and risk for tuberculosis (TB) in hemodialysis (HD) patients. All active TB cases were recorded during a 36-month follow-up of 272 (193 male and 79 female) HD patients. Entering the study, HD patients were tested with tuberculin and 2,4-dinitrochlorobenzene, and a cell-mediated immunity (CMI) index was estimated. Relative risks (RR) for TB were calculated considering subjects from the background general population as a reference group. The independent effect of age, BMI and tuberculin sensitivity was determined using Cox's proportional hazard model. Female HD patients presented significantly lower CMI indices and rates of positive Mantoux tests, but higher rates of DM, as compared to males. The male:female ratio in TB for the general and HD patients population was 1.8 and 0.6, respectively. There was a significantly lower TB prevalence in male as compared to female HD patients (7.7% vs. 11.3%), and a subsequent female predominance in risk for TB in those HD patients aged <49 and 50-69 years (M:F adjusted relative risk 0.67 and 0.53) was recorded. In contrast to the general population, there is a female predominance among dialysis TB patients younger than 70 years associated with the coexistence of DM. Female gender should always be considered as a risk factor when evaluating diabetic HD patients for active TB.


Improved podophyllotoxin production by transformed cultures of Linum album.
Various cell and hairy root cultures of L. album were developed and analyzed for podophyllotoxin content. Transformed callus and hairy root cultures developed from infection of stem portions of in vitro-germinated L. album plant with Agrobacterium rhizogenes NCIM 5140 strain were selected on the basis of high podophyllotoxin content and growth. Based on the integration of Ri T(L)-DNA and T(R)-DNA, integration of only the ags and not the rol gene in transformed cell culture indicated fragmented integration pattern. The effect of different cultivation media and carbon source on growth and podophyllotoxin production were studied in shake-flask suspension cultures. Detailed batch growth and production kinetics with sugar consumption profile were also established. Maximum volumetric productivity of 4.40 and 2.75 mg/L per day was obtained in cell suspension and hairy root cultures, respectively.


Immunogenicity and Safety of Yellow Fever Vaccine (Stamaril) When Administered Concomitantly With a Tetravalent Dengue Vaccine Candidate in Healthy Toddlers at 12-13 Months of Age in Colombia and Peru: A Randomized Trial.
Dengue and yellow fever (YF) viruses are closely related members of the Flaviviridae family. Given the inherent similarities between the YF vaccine and dengue vaccine (CYD-TDV) candidate, it is possible that the latter could interfere with the response to the licensed YF vaccine when coadministered. In this randomized, observer-blind, controlled, phase III trial, conducted in Colombia and Peru, 787 toddlers were administered YF vaccine concomitantly with CYD-TDV (group 1) or placebo (group 2), followed by CYD-TDV after 6 and 12 months. YF and dengue neutralizing antibody titers were determined using a 50% plaque reduction neutralization test. Noninferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates [(YF + CYD-TDV) - YF alone] was greater than -10%. The safety of both vaccines was also assessed. Concomitant administration of YF with either CYD-TDV or placebo yielded YF seroconversion rates of 100.0% and 99.7%, respectively. The difference in YF seroconversion rates between the 2 groups was 0.33% (95% confidence interval:0.98; 1.87), demonstrating that the immune response against YF administered concomitantly with CYD-TDV was noninferior to YF administered with placebo. After 2 injections of CYD-TDV, the percentage of participants with dengue titres ≥10 (1/dil) for the 4 dengue serotypes were 91.2%-100% for group 1 and 97.2%-100% in group 2. There were no safety concerns during the study period. Concomitant administration of YF vaccine with CYD-TDV has no relevant impact on the immunogenicity or safety profile of the YF vaccine.


Associations between multiple environmental exposures and Glutathione S-Transferase P1 on persistent wheezing in a birth cohort.
To determine the impact of environmental exposures (diesel exhaust particle [DEP], environmental tobacco smoke [ETS], and mold) that may contribute to oxidative stress on persistent wheezing in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort and to determine how the impact of these exposures is modified by the GST-P1 Ile105Val polymorphism. A land-use regression model was used to derive an estimate of each child's DEP exposure. ETS exposure was determined by questionnaire data. Each child's home was evaluated for visible mold by a trained professional. Children in the CCAAPS cohort were genotyped for the GST-P1 polymorphism (n = 570). Persistent wheezing was defined as wheezing at both 12 and 24 months. High DEP exposure conferred increased risk for wheezing phenotypes but only among the Val(105) allele carriers. Infants with multiple exposures were significantly more likely to persistently wheeze despite their genotype. There is evidence for an environmental effect of DEP among carriers of the GST-P1 Val(105) allele in the development of persistent wheezing in children. The protective effect of the GST-P1 Ile(105) genotype may be overwhelmed by multiple environmental exposures that converge on oxidative stress pathways.


Nitrogen-Fluorine co-doped TiO2/SiO2 nanoparticles for the photocatalytic degradation of acrylonitrile: Deactivation and regeneration.
In this study, we investigated the deactivation kinetics and mechanism of N-F-TiO2/SiO2 nanopowder as a model photocatalyst for the purpose of facilitating the photocatalytic degradation of acrylonitrile (AN) in aqueous environment. Prior research has already displayed the proficient degradation of AN through the utilization of N-F-TiO2/SiO2 catalysts, revealing a degradation efficiency of 81.2% within a span of 6 min at an initial AN concentration of 10 mg/L. Multiple variables including the initial AN concentration, illumination intensity, and initial pH value were extensively analyzed during the degradation process. The kinetics of photocatalytic degradation of AN, facilitated by the N-F-TiO2/SiO2 photocatalyst, were modeled by fitting the pseudo first-order reaction kinetics to each individual factor. Furthermore, the adverse effect of catalyst poisoning during the photocatalytic breakdown of AN using the N-F-TiO2/SiO2 photocatalyst was analyzed through a range of different techniques including SEM, XPS, BET, XRD, TG, and NH3-TPD. The incorporation of findings from these diverse techniques revealed that, the primary factors contributing to the photocatalyst's poisoning were as follows: (i) During the degradation process, the build-up of intermediate molecules on active sites hindered their functionality, leading to a decrease in the efficiency of the photocatalytic reaction, (ii) Carbonaceous deposits formed when the catalyst's pore structure was obstructed by pollutants or intermediate products that had not undergone timely photocatalytic breakdown and (iii) The persistent erosion of active sites due to hydraulic forces resulted in inadequate performance of the N-F-TiO2/SiO2 photocatalyst in aqueous solutions. A comprehensive analysis of the deactivation kinetics was conducted, deciding in the formulation of a detailed poisoning mechanism for the N-F-TiO2/SiO2 photocatalyst. Additionally, we explored the catalysts regeneration, involving thermal treatment, ultrasonic irradiation, and catalyst reloading. This study not only advances our insight into the waning performance of catalysts in aqueous media but also establishes a conceptual framework for extrapolating analogous deactivation dynamics in other catalysts, grounded in precedent experimental knowledge. This research contributes to the development of a deactivation model for catalysts in the aqueous environment, based on existing experimental research, providing a theoretical framework for understanding the deactivation process of photocatalysts.


Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect.
Pulmonary hypertension (PH) is an enigmatic vascular syndrome characterized by increased pulmonary arterial pressure and adverse remodelling of the pulmonary arterioles and often of the right ventricle. Drawing parallels with tumourigenesis, recent endeavours have explored the relationship between metabolic dysregulation and PH pathogenesis. We will discuss the general mechanisms by which cellular stressors such as hypoxia and inflammation alter cellular metabolism. Based on those principles, we will explore the development of a corresponding metabolic pathophenotype in PH, with a focus on WHO Groups I and III, and the implications that these alterations may have for future treatment of this disease. Investigation of metabolic dysregulation in both the pulmonary vasculature and right ventricle during PH pathogenesis has provided a more unifying understanding of how disparate disease triggers coordinate end-stage disease manifestations. Namely, as defined originally in various cancers, the Warburg effect describes a chronic shift in energy production from mitochondrial oxidative phosphorylation to glycolysis. In many cases, this Warburg phenotype may serve as a central causative mechanism for PH progression, largely driving cellular hyperproliferation and resistance to apoptosis. Consequently, new therapeutic strategies have been increasingly pursued that target the Warburg phenotype. Finally, new technologies are increasingly becoming available to probe more completely the complexities of metabolic cellular reprogramming and may reveal distinct metabolic pathways beyond the Warburg effect that drive PH. Studies of metabolic dysregulation in PH are just emerging but may offer powerful therapeutic means to prevent or even reverse disease progression at the molecular level.


How to uncover the covert saccade during the head impulse test.
The appearance of "covert" saccades in the head impulse test in patients with vestibular loss may lead to diagnostic misinterpretations. Here, we demonstrate a procedure that can convert covert eye saccades to overt when performing the head impulse test. Patients with known vestibular deficits that have covert saccades during head impulse test. Diagnostic: random and sudden changes of the amplitude (degree of head turn) when performing the head impulse test. Evaluation of bedside test with video recording and registration from video head impulse test (v-HIT). A video recording and registration from v-HIT that demonstrate the covert saccades of a subject and how the overt saccade is uncovered by changing the amplitude of the head impulse. Five cases are briefly presented. By performing the head impulse test with random amplitudes, overt saccades may become detectable and advance accuracy in bedside diagnosis of vestibular deficits.


Comparative study of the microstructural and magnetic properties of fly ashes obtained from different thermal power plants in West Bengal, India.
This paper deals with the physical nature of the fly ashes obtained from two thermal power plants, situated in West Bengal, India. The fly ash samples are characterized by using comprehensive techniques with an emphasis on their ultrafine nature. The particle sizes of the samples are estimated using scanning electron microcopy (SEM) and found to lie within 0.18-5.90 μm. For morphology and compositional analysis, we also use SEM coupled with energy dispersive X-ray spectrometry. From X-ray study of the fly ashes the nature of conglomeration is seen to be crystalline, and the major components are mullite (Al6Si2O13) and quartz (SiO2). The magnetic measurement of the fly ash samples was carried out by SQUID magnetometer. (57)Fe Mössbauer spectra are obtained using a conventional constant-acceleration spectrometer with a (57)Co/Rh Mössbauer source. The hyperfine parameters obtained, in general, support the findings as made from XRD analysis and provide a quantitative measure of different iron ions present in the samples. The paper presents experimental data on the physical aspects of the fly ash samples of the thermal power plants which comprise coarse, fine, and ultrafine magnetic particulate materials and attempts to provide an exhaustive analysis.


Compendium of instruments measuring patient satisfaction with nursing care.
Recent changes in health care delivery have encouraged a search for comprehensive and established measures of patient satisfaction with nursing care (PSNC), which studies have found to be the most important predictor of overall satisfaction with hospital care and an important indicator of outcome. Twenty-one current PSNC instruments are described in a compendium, which provides information on the developer and the date of publication or first use, types of items and subscales, mode of administration, reliability and validity formulas, and availability.


The long and short of mistress relationships: Sex-differentiated mate preferences reflect a compromise of mating ideals.
Evolved mate preferences have taken center stage in evolutionary psychology research, yet this literature has been fairly muted on mate preferences for extrapair partners. Here, we examined the mate preferences for mistress relationships (the traits that men prioritize in a mistress and mistresses prioritize in their male partners) and compared these preferences to those of short- and long-term relationships. In two studies (NStudy 1a = 104, NStudy 1b = 191), we derived dimensions of mate preferences through exploratory factor analyses. In subsequent studies (NStudy 2 = 219, NStudy 3 = 101), we employed a budget allocation paradigm, where participants designed their ideal mates for different relationship types (short-term, long-term, and mistress relationships). Whereas men focused on fulfilling short-term mating ideals (by prioritizing physical attractiveness) in a mistress relationship, women focused on fulfilling long-term (but also some short-term) mating ideals (prioritizing both physical attractiveness and social status) for a mistress relationship. Findings indicate that mistress relationships reflect a compromise of men's and women's (conflicting) mating ideals and contribute to an understanding of relationships that are neither completely short- nor long-term in nature.


Amphetamine and haloperidol modulate preprotachykinin A mRNA expression in rat nucleus accumbens and caudate-putamen.
In situ hybridization was used to measure the effect of repeated amphetamine (1.5 mg/kg) and haloperidol (0.5 mg/kg) treatment for 7 days on the expression of preprotachykinin A (PPT-A) mRNA in rat nucleus accumbens (Acb) and caudate-putamen (CPu). Amphetamine elevated the level of PPT-A mRNA in Acb, but not in CPu. Haloperidol decreased the levels in Acb shell and CPu, but not in Acb core. Haloperidol injected together with amphetamine, prevented the amphetamine-induced increase in PPT-A mRNA expression in both Acb core and shell.


Single pulse stimulation of guinea-pig vas deferens and the presynaptic receptor hypothesis.
1 The effect of phenoxybenzamine on the efflux of [3H]-noradrenaline and the mechanical response to single pulse excitation of superfused guinea-pig vas deferens was determined to examine the validity of the currently accepted hypothesis of a presynaptic negative feedback system on adrenergic nerve terminals. 2 The adrenoceptor antagonist enhanced both the outflow of tritium and the mechanical response to single pulse stimulation. The efflux of labelled material and the responses to 4 pulses were also enhanced, as expected. 3 Blockade of neuronal and extraneuronal uptake did not by itself increase nerve-induced outflow or the mechanical response nor dated within the framework of a hypothesis that proposes that the enhancement of response and tritium efflux by phenoxybenzamine results from blockade of a feedback system whereby noradrenaline released by previous impulses inhibits its own subsequent release.


The free-energy cost of interaction between DNA loops.
From the viewpoint of thermodynamics, the formation of DNA loops and the interaction between them, which are all non-equilibrium processes, result in the change of free energy, affecting gene expression and further cell-to-cell variability as observed experimentally. However, how these processes dissipate free energy remains largely unclear. Here, by analyzing a mechanic model that maps three fundamental topologies of two interacting DNA loops into a 4-state model of gene transcription, we first show that a longer DNA loop needs more mean free energy consumption. Then, independent of the type of interacting two DNA loops (nested, side-by-side or alternating), the promotion between them always consumes less mean free energy whereas the suppression dissipates more mean free energy. More interestingly, we find that in contrast to the mechanism of direct looping between promoter and enhancer, the facilitated-tracking mechanism dissipates less mean free energy but enhances the mean mRNA expression, justifying the facilitated-tracking hypothesis, a long-standing debate in biology. Based on minimal energy principle, we thus speculate that organisms would utilize the mechanisms of loop-loop promotion and facilitated tracking to survive in complex environments. Our studies provide insights into the understanding of gene expression regulation mechanism from the view of energy consumption.


Neuromodulation for Pain Management.
Pain is a salient and complex sensory experience with important affective and cognitive dimensions. The current definition of pain relies on subjective reports in both humans and experimental animals. Such definition lacks basic mechanistic insights and can lead to a high degree of variability. Research on biomarkers for pain has previously focused on genetic analysis. However, recent advances in human neuroimaging and research in animal models have begun to show the promise of a circuit-based neural signature for pain. At the treatment level, pharmacological therapy for pain remains limited. Neuromodulation has emerged as a specific form of treatment without the systemic side effects of pharmacotherapies. In this review, we will discuss some of the current neuromodulatory modalities for pain, research on newer targets, as well as emerging possibility for an integrated brain-computer interface approach for pain management.


Optimizing the synthesis of dimeric peptides: influence of the reaction medium and effects that modulate kinetics and reaction yield.
Peptides are remarkably interesting alternatives to several applications. In particular, antimicrobial sequences have raised major interest of the scientific community due to the resistance acquired by commonly used antibiotics. Amongst these, some dimeric peptides have shown very promising characteristics as strong biological activities and resistance against degradation by peptidases. However, despite such promising characteristics, a relatively small number of studies address dimeric peptides, mainly due to the synthesis-related obstacles in their production, whereas the well-implemented routines of solid phase peptide synthesis-which includes the possibility of automation-makes life significantly easier. Here, we present kinetic investigations of the dimerization of a cysteine-containing sequence to obtain the homodimeric antimicrobial peptide homotarsinin. Based on the structural and membrane interaction data already available for the dimer and its monomeric chain, we have proposed distinct dimerization protocols in selected environments, namely, aqueous buffer, TFE:H2O and micellar solutions. The experimental results were adjusted by a theoretical model. Both the kinetic profiles and the reaction yields are dependent on the reaction medium, clearly indicating that aggregation, peptide structure, and peptide-membrane interactions play major roles in the formation of the disulfide bond. Finally, the rationalization of the different aspects addressed here is expected to contribute to research and applications that demand the obtainment of dimeric peptides.