Immunosuppressive therapy of organ-specific nephritic autoimmune diseases with 15-deoxyspergualin.
According to its immunopharmacological profile, 15-deoxyspergualin (15-DOS) has been investigated as to its disease-modifying activity on HgCl2-induced glomerulonephritis (GN) and on tubulointerstitial nephritis (TIN) in Brown-Norway rats. Both models are induced autoimmune disorders in which afflicted animals display high levels of serum autoantibodies directed against the glomerular or tubular basement membrane (GBM or TBM), respectively. The diseases are manifested by high serum creatinine and urea levels with severe proteinuria. In the model of HgCl2-GN, administration of 15-DOS clearly led to a reduction of proteinuria and decreased the amount of rat IgG attached to the GBM. Furthermore, a therapeutic effect could be demonstrated when 15-DOS was given after the appearance of clinical symptoms. Not only urine-protein values but also anti-laminin antibodies returned to normal levels. Also in the experimental TIN-model, 15-DOS, either given during the induction phase, or even late in the onset of the disease, strongly prevented the proteinuria of this autoimmune disease and inhibited the formation of autoantibodies to TBN.


New methodological improvements in the Microtox® solid phase assay.
The classic Microtox® solid phase assay (MSPA) based on the inhibition of light production of the marine bacteria recently renamed Aliivibrio fischeri suffers from various bias and interferences, mainly due to physico-chemical characteristics of the tested solid phase. To precisely assess ecotoxicity of sediments, we have developed an alternative method, named Microtox® leachate phase assay (MLPA), in order to measure the action of dissolved pollutants in the aqueous phase. Two hypotheses were formulated to explain the observed difference between MSPA and MLPA results: a real ecotoxicity of the solid phase or the fixation of bacteria to fine particles and/or organic matter. To estimate the latter, flow cytometry analyses were performed with two fluorochromes (known for their ability to stain bacterial DNA), allowing correction of MSPA measurements and generation of new (corrected) IC50. Comparison of results of MLPA with the new IC50 MSPA allows differentiating real ecotoxic and fixation effect in classic MSPA especially for samples with high amount of fines and/or organic matter.


Neuroprotective effect of Berberine Nanoparticles Against Seizures in Pentylenetetrazole Induced Kindling Model of Epileptogenesis: Role of Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Mechanisms.
There is an unmet need to develop alternative therapeutic strategies to not only restrain seizures but also to alleviate the underlying pathologies and sequelae. Berberine (BBR), an isoquinoline alkaloid, has shown promising effect in the kindling model of epileptogenesis, but due to the poor oral bioavailability its clinical application is limited. So, the present study was designed to study the neuroprotective effect of BBR nanoparticles (enhanced bioavailability as compared to BBR) against seizures in pentylenetetrazole (PTZ) induced kindling model of epileptogenesis. Kindling model was established in male Wistar rats by intraperitoneal (i.p.) administration of PTZ (30 mg/kg) on every alternate day till the animal became fully kindled or till 6 weeks. Three doses of BBR (50, 100, and 200 mg/kg) and nano-BBR (25, 50, 100 mg/kg) were studied for seizure score, percentage of animal kindled, histopathological score, oxidative stress, inflammation, and apoptosis in PTZ treated rats by conducting cytokines, gene expression and protein expression analysis. BBR nanoparticles showed significant effect on the seizure score and percentage of animal kindled, histopathological score, neurobehavioral parameters (Forced swim test, Rotarod), oxidative (MDA, SOD, GSH, GPx) and inflammatory (IL-1beta, TNF-alpha) parameters, apoptotic parameters (Bax and iNOS), and gene (Nrf2, NQO1, HO1) and protein expression (Nrf2) as compared to both PTZ and BBR. BBR nanoparticles showed neuroprotective effect in PTZ induced kindling model of epileptogenesis and proves to be a promising antiepileptogenic therapy for the patients who are at high risk of developing seizures.


Like No. 1 Mike Leavitt, most atop the 100 Most Powerful wield their influence from D.C., and help determine how money is spent.
Modem Healthcare's fourth annual ranking of the 100 Most Powerful People in Healthcare boasts an eclectic group. Those who practice medicine and teach it to others share the list with presidents of companies and the president of the country. Lawmakers and information technology risk-takers round out a roster that mirrors the industry's diversity and highlights the many ways people contribute to healthcare.


Generation of genome-edited mouse epiblast stem cells via a detour through ES cell-chimeras.
Conventionally, mouse epiblast stem cells (EpiSCs) are derived directly from the epiblast or ectoderm germ layer of the post-implantation embryo. Self-renewing and multipotent EpiSC-like stem cells can also be derived by the conversion of embryonic stem cells (ESCs) via the provision of culture conditions that enable the maintenance of the EpiSCs. Here, we outline an experimental procedure for deriving EpiSCs from post-implantation chimeric embryos that are generated using genome-edited ESCs. This strategy enables the production of EpiSCs where (i) no genetically modified animals or ESCs are available, (ii) the impact of the genetic modification on post-implantation development, which may influence the property of the EpiSCs, is requisite knowledge for using the EpiSC for a specific investigation, and (iii) multiple editing of the genome is desirable to modify the biological attributes of the EpiSCs for studying, for example, the gene network activity on the trajectory of lineage differentiation and tissue morphogenesis.


A study of hydrogen peroxide generation by, and antioxidant activity of, Granuflex (DuoDERM) Hydrocolloid Granules and some other hydrogel/hydrocolloid wound management materials.
The effect of Granuflex Hydrocolloid Granules (0.01-0.50% w/v) on the rate of proliferation of murine (L929) fibroblasts was examined. The dose-response curve showed a significant (P < 0.02) pro-proliferant effect at 0.05%, and a significant (P < 0.02) antiproliferant effect at 0.50%, mirroring the dose-response curve produced by hydrogen peroxide in the concentration range 10(-9) - 10(-4) mol/l. The antiproliferant effect at 0.20% w/v was abolished by catalase, suggesting that the biological activity of Granuflex was mediated by the in situ generation of hydrogen peroxide. Formation of hydrogen peroxide by Granuflex was confirmed by performing the scopoletin-horseradish peroxidase assay in the presence and absence of catalase. The total concentration of hydrogen peroxide detected was about 8 x 10(-6) mol/l (using 0.5% w/v Granuflex) after 48 h at 37 degrees C. In contrast, when hydrogen peroxide itself was added to L929 cultures, a similar antiproliferant activity was observed at concentrations between 10(-4) and 10(-5) mol/l. These results suggested that Granuflex was undergoing autoxidation in the culture medium, and hence that it might possess antioxidant activity. In assays for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH), Granuflex, and two other hydrocolloid dressings (Comfeel Powder and Bard Absorption Dressing) showed significant ability to reduce DPPH to DPPH2. These three dressings also displayed superoxide scavenging activity in a nitroblue tetrazolium reduction assay. We conclude that, in addition to providing a moist wound-healing environment, Granuflex and certain other hydrocolloids might contribute to the establishment and maintenance of the reducing environment necessary for energy production and hence cell division.(ABSTRACT TRUNCATED AT 250 WORDS)


The evolution of burn fluid resuscitation.
This article reviews the important developments, recent and historical, in burn fluid resuscitation. Modern managements, debates, and research directions are discussed, with a key question of how to transcend the current therapeutic plateau.


High dose gonadotropin stimulation increases endometrial thickness but this gonadotropin induced thickening does not have an effect on implantation.
Endometrial thickness <8 mm is related with lower pregnancy rates. This raises the question if endometrial thickness can be increased by gonadotropin stimulation to increase estradiol (E2) concentration and if such an artificial thickening of the endometrium has an effect on implantation. A model to address this question is the comparison of endometrial thickness and outcome parameters in conventional gonadotropin stimulated IVF (cIVF) compared to unstimulated natural cycle IVF (NC-IVF). Retrospective study including 235 cIVF and 616 NC-IVF cycles without embryo selection and with fresh transfer on day 2 and 3 from 2015 to 2019. Endometrial and E2 measurements were included and analysed between day -4 and -2 (0 = day of aspiration). The effects of E2 on endometrial thickness, endometrial growth and the effect of endometrial thickness on implantation rates and live births were analysed. Endometrial thickness was found to be higher in cIVF compared to NC-IVF (p < 0.001). On day -2, the day when ovulation was triggered, mean endometrial thickness was 9.75 ± 2.05 mm and 8.12 ± 1.66 mm, respectively. The increase in endometrial thickness slowed down with increasing E2 concentrations (time x estradiol concentration: -0.19, p = 0.010). Implantation rates were not significantly different in cIVF and NC-IVF cycles (clinical pregnancy rate: 19.1% vs. 15.4% p = 0.2; live birth rate: 12.8% vs. 11.7%, p = 0.8). Endometrial growth dynamic is different and endometrium is thicker in cIVF compared to NC-IVF. Pregnancy and live birth rates are not different. Gonadotropin induced thickening of the endometrium does not appear to improve implantation.


Biodegradable film based on cress seed mucilage, modified with lutein, maltodextrin and alumina nanoparticles: Physicochemical properties and lutein controlled release.
In this study, maltodextrin (MDex), lutein pigment (Lut) and alumina (Al) were used to modify biodegradable film based on cress seed mucilage (Muc/MDex/Lut/Al). Central composite design (CCD) was used to study the effects of MDex, Lut and Al on the physical and chemical properties of the mucilage based film. The physicochemical, mechanical, antimicrobial and structural properties of the films were studied by various techniques such as FTIR, SEM, and XRD and TGA. The release of lutein from the film was investigated at 25 °C for 15 days. The results showed that lutein, alumina and maltodextrin increased the film thickness and lutein decreased the solubility and moisture content of the film. Maltodextrin improved the mechanical properties of the film and lutein reduced the film's flexibility. Lutein greatly increased its antioxidant properties, but alumina slightly increased its antioxidant properties. Lutein, alumina and maltodextrin improved the antibacterial properties of the film. Muc/MDex/Lut/Al film showed 26 ± 0.5 and 23 ± 0.8 mm non-growth halo against to Staphylococcus aureus and Escherichia coli, respectively. Maltodextrin filled the surface cracks, but lutein increased the surface cracks of mucilage film. The amorphous structure of the pure cress seed mucilage film was confirmed by XRD, which the alumina and lutein gave crystalline properties in the film. Maltodextrin and alumina increased the thermal stability of the film. The release results showed that the release rate of lutein depends on the structure of the film and by changing the structure of the film, the release rate can be purposefully controlled according to the required release rate.


Button vesicostomy: a continent urinary stoma.
A modified technique of vesicostomy is described using a gastrostomy button, which could be used as a continent urinary stoma in children with incomplete voiding. From 1998 to 2005, 21 children aged between 4 days and 16 years underwent insertion of button vesicostomy to permit bladder drainage. They had incomplete bladder emptying and clean intermittent urethral catheterization (CIC) could not be established. In six of 23 procedures, the button was placed through a classical vesicostomy (3) or via a suprapubic catheter tract (3). In 17, a standardized technique of button vesicostomy stoma formation was used. The median follow up was 2.5 years (0.75-8 years). Patients were selected on the basis of clinical need. Idiopathic hypotonic bladder was the most common indication (9), followed by anorectal malformation (5), neuropathic bladder and posterior urethral valves (2 each), traumatic rupture of urethra (1), visceral myopathy (1) and posterior urethritis (1). Granuloma formation around vesicostomy button was observed in five patients. Local infection was observed in three patients and urinary tract infection in four. No peri-button leakage occurred in the standardized button stomas but was seen in all three of the buttons placed in classical vesicostomies, and transient leakage occurred in one of the three patients with a button placed via a suprapubic catheter tract. The median duration of use of vesicostomy button was 11 months (2-30 months). In eight patients, bladder function improved and intermittent drainage was no longer required. Three patients are still using the button, four progressed to Mitrofanoff, four started CIC per urethra, and two reverted to continuous drainage. Button vesicostomy is a useful addition to the options available for a catheterizable continent urinary stoma in children in the short or medium term. The risk of major complications was low although minor complications were common, and the technique was well accepted by patients and parents.


Circulating inflammatory cells are associated with vein graft stenosis.
Infrainguinal autogenous vein grafts are especially prone to narrowing and failure, and both inflammatory and thrombotic pathways are implicated. Platelets and monocytes are the key thrombo-inflammatory cells that arrive first at sites of vascular injury. These cells have potent interactions that recruit and activate one another, propagating thrombotic and inflammatory responses within the vessel wall. We therefore hypothesized that elevated levels of platelet-monocyte aggregates (PMA) might be associated with stenosis, and could possibly discriminate between patients with or without vein graft stenosis. Thirty-six vascular surgery patients were studied, in a stable quiescent period after infrainguinal autogenous vein graft bypasses for occlusive disease. Eighteen patients had hemodynamically significant graft stenoses confirmed by imaging, and 18 were free from stenosis. The level of PMA in whole blood was quantified after blood draw using two-color flow cytometry. Three measurements were made per sample: the basal, in-vivo level of aggregates (baseline PMA); the predisposition to spontaneously generate PMA (spontaneous PMA); and PMA generation by the addition of exogenous thrombin receptor-activating peptide (stimulated PMA). The baseline, in-vivo level of PMA was estimated by immediate flow analysis. The predisposition to spontaneously generate PMA was measured after in vitro incubation. Responsiveness to thrombin stimulation of the blood was quantified by the in vitro dose response to an exogenous thrombin receptor-activating peptide (sfllrn). Baseline PMA levels were similar in patients with vein graft stenosis vs nonstenosis (14.8% ± 3.2 vs 10.1% ± 1.5, respectively, mean ± SEM). However, patients with stenosis showed higher spontaneous PMA levels (58.5% ± 4.5 vs 28.3% ± 4.3; P < .001) and higher stimulated PMA levels (P < .001; analysis of variance). Covariables of smoking, diabetes, statin, or antithrombotic therapy could not account for these differences. Platelet-monocyte reactivity may play a role in the development of vein graft stenoses. Those with/without stenosis differed primarily in their threshold, or predisposition to form aggregates (spontaneous PMA), while their basal circulating levels of PMA (baseline PMA) were similar. These measurements may unmask pathologic differences in thrombo-inflammatory responsiveness that are not apparent in basal measurements. Understanding the causes and mechanisms leading to abnormal platelet-monocyte responses may improve approaches to predicting or preventing vein graft stenosis.


Oxidative coupling of a feruloyl-arabinoxylan trisaccharide (FAXX) in the walls of living maize cells requires endogenous hydrogen peroxide and is controlled by a low-Mr apoplastic inhibitor.
Feruloyl-polysaccharides can be oxidatively coupled in isolated cell walls by peroxidase plus exogenous H(2)O(2) in vitro, but the extent to which similar reactions may occur in the apoplast in vivo was unclear. Numerous cellular factors potentially control feruloyl coupling in vivo, and their net controlling influence is not readily studied in vitro. Therefore, we have monitored apoplastic feruloyl coupling in cultured maize cells in vivo using a radiolabelled model substrate, 5-O-feruloyl-alpha-L: -arabinofuranosyl-(1-->3)-beta-D: -xylopyranosyl-(1-->4)-D: -xylose (FAXX). FAXX was expected to permeate the wall and to undergo reactions analogous to those normally exhibited by apoplastic feruloyl-polysaccharides in vivo. Little difference was found between the fates of [feruloyl-(14)C]FAXX and [pentosyl-(3)H]FAXX, indicating negligible apoplastic hydrolase or transferase activities. Very little radioactivity entered the protoplasm. Maize cells that had recently been washed in fresh medium were able to bind most of the FAXX (90%) in their cell walls, regardless of the age of the culture. During wall-binding, the [(14)C]feruloyl groups were converted to [(14)C]dehydrodiferulates and larger coupling products, as revealed by TLC after alkaline hydrolysis. As expected for an oxidative reaction, wall-binding was delayed by added anti-oxidants (ascorbate, ferulate, sinapate, chlorogenate or rutin). It was also completely inhibited by iodide, an H(2)O(2)-scavenger, indicating a role for peroxidase rather than oxidase. The observations indicate that oxidative coupling of feruloyl groups occurred within the cell wall, dependent on endogenous apoplastic H(2)O(2) and wall-localised peroxidase, in vivo. Cells that had not recently been washed in fresh medium were much less able to bind FAXX, indicating the presence in the apoplast of an endogenous inhibitor of oxidative coupling. This inhibitor was of low M(r), was destroyed by heating, and remained in the aqueous phase (pH approximately 3.5) when shaken with ethyl acetate. Its effectiveness was not altered by ascorbate oxidase. It is thus a small, heat-labile, hydrophilic inhibitor (not ascorbate) which we suggest plays a natural role in the control of wall cross-linking, and thus potentially in the control of cell growth.


Experimental validation of a portable tidal volume indicator for bag valve mask ventilation.
Short-term emergency ventilation is most typically accomplished through bag valve mask (BVM) techniques. BVMs like the AMBU® bag are cost-effective and highly portable but are also highly prone to user error, especially in high-stress emergent situations. Inaccurate and inappropriate ventilation has the potential to inflict great injury to patients through hyper- and hypoventilation. Here, we present the BVM Emergency Narration-Guided Instrument (BENGI) - a tidal volume feedback monitoring device that provides instantaneous visual and audio feedback on delivered tidal volumes, respiratory rates, and inspiratory/expiratory times. Providing feedback on the depth and regularity of respirations enables providers to deliver more consistent and accurate tidal volumes and rates. We describe the design, assembly, and validation of the BENGI as a practical tool to reduce manual ventilation-induced lung injury. The prototype BENGI was assembled with custom 3D-printed housing and commercially available electronic components. A mass flow sensor in the central channel of the device measures air flow, which is used to calculate tidal volume. Tidal volumes are displayed via an LED ring affixed to the top of the BENGI. Additional feedback is provided through a speaker in the device. Central processing is accomplished through an Arduino microcontroller. Validation of the BENGI was accomplished using benchtop simulation with a clinical ventilator, BVM, and manikin test lung. Known respiratory quantities were delivered by the ventilator which were then compared to measurements from the BENGI to validate the accuracy of flow measurements, tidal volume calculations, and audio cue triggers. BENGI tidal volume measurements were found to lie within 4% of true delivered tidal volume values (95% CI of 0.53 to 3.7%) when breaths were delivered with 1-s inspiratory times, with similar performance for breaths delivered with 0.5-s inspiratory times (95% CI of 1.1 to 6.7%) and 2-s inspiratory times (95% CI of -1.1 to 2.3%). Audio cues "Bag faster" (1.84 to 2.03 s), "Bag slower" (0.35 to 0.41 s), and "Leak detected" (43 to 50%) were triggered close to target trigger values (2.00 s, 0.50 s, and 50%, respectively) across varying tidal volumes. The BENGI achieved its proposed goals of accurately measuring and reporting tidal volumes delivered through BVM systems, providing immediate feedback on the quality of respiratory performance through audio and visual cues. The BENGI has the potential to reduce manual ventilation-induced lung injury and improve patient outcomes by providing accurate feedback on ventilatory parameters.


Solid Halide Electrolytes with High Lithium-Ion Conductivity for Application in 4 V Class Bulk-Type All-Solid-State Batteries.
New lithium halide solid-electrolyte materials, Li3 YCl6 and Li3 YBr6 , are found to exhibit high lithium-ion conductivity, high deformability, and high chemical and electrochemical stability, which are required properties for all-solid-state battery (ASSB) applications, particularly for large-scale deployment. The lithium-ion conductivities of cold-pressed powders surpass 1 mS cm-1 at room temperature without additional intergrain or grain boundary resistances. Bulk-type ASSB cells employing these new halide solid electrolyte materials exhibit coulombic efficiencies as high as 94% with an active cathode material of LiCoO2 without any extra coating. These superior electrochemical characteristics, as well as their material stability, indicate that lithium halide salts are another promising candidate for ASSB solid electrolytes in addition to sulfides or oxides.


[Description of Simulium (Edwardsellum) kilibanum sp. n. and its position in the S. damnosum complex (Diptera: Simuliidae) (author's transl)].
Male, female, pupa and larva of a new species of the Simulium damnosum complex collected in tributaries of lake Tanganyika in the Kivu Province of Zaire are described. The position of the new species in the S. damnosum complex is discussed.


An eye on light-sheet microscopy.
This chapter introduces the principles and advantages of selective plane illumination microscopy (SPIM) and compares it to commonly used epifluorescence or confocal setups. Due to the low phototoxicity, speed of imaging, high penetration depth, and spatiotemporal resolution, SPIM is predestined for in vivo imaging but can as well be used for in toto analysis of large fixed samples. Key points of light-sheet microscopy are highlighted and discussed priming the investigator to choose the best suitable system from the large collection of possible SPIM setups. Mounting of samples is shown and the demands for data acquisition, processing, handling, and visualization are discussed.


Racial differences in the association of accelerated aging with future cardiovascular events and all-cause mortality: the coronary artery risk development in young adults study, 2007-2018.
Variability of Cardiovascular disease (CVD) risk, including racial difference, is not fully accounted for by the variability of traditional CVD risk factors. We used a multiple biomarker model as a framework to explore known racial differences in CVD burden. We measured associations between accelerated aging (AccA) measured by a combination of biomarkers, and cardiovascular morbidity and all-cause mortality using data from the Coronary Artery Risk Development in Young Adults study (CARDIA). AccA was defined as the difference between biological age, calculated using biomarkers with the Klemera and Doubal method, and chronological age. Using logistic regression, we assessed overall and race-specific associations between AccA, CVD, and all-cause mortality. Among our cohort of 2959 Black or White middle-aged adults, after adjustment, a one-year increase in AccA was associated with increased odds of CVD (Odds Ratio (OR) = 1.04; 95% CI: 1.02, 1.06), stroke (OR = 1.12; 95% CI: 1.07, 1.17), and all-cause mortality (OR = 1.05; 95% CI: 1.02, 1.08). We did not find significant overall racial differences, but we did find race by sex differences where Black men differed markedly from White men in the strength of association with CVD (OR = 1.06, 95% CI: 1.01, 1.12). We provide evidence that AccA is associated with future CVD.


Selective fluorescence response and magnetic separation probe for 2,4,6-trinitrotoluene based on iron oxide magnetic nanoparticles.
Despite the rapid development of nanomaterials and nanotechnology, it is still desirable to develop novel nanoparticle-based techniques which are cost-effective, timesaving, and environment-friendly, and with ease of operation and procedural simplicity, for assay of target analytes. In the work discussed in this paper, the dye fluorescein isothiocyanate (FITC) was conjugated to 1,6-hexanediamine (HDA)-capped iron oxide magnetic nanoparticles (FITC-HDA Fe3O4 MNPs), and the product was characterized. HDA ligands on the surface of Fe3O4 MNPs can bind 2,4,6-trinitrotoluene (TNT) to form TNT anions by acid-base pairing interaction. Formation of TNT anions, and captured TNT substantially affect the emission of FITC on the surface of the Fe3O4 MNPs, resulting in quenching of the fluorescence at 519 nm. A novel FITC-HDA Fe3O4 MNPs-based probe featuring chemosensing and magnetic separation has therefore been constructed. i.e. FITC-HDA Fe3O4 MNPs had a highly selective fluorescence response and enabled magnetic separation of TNT from other nitroaromatic compounds by quenching of the emission of FITC and capture of TNT in aqueous solution. Very good linearity was observed for TNT concentrations in the range 0.05-1.5 μmol L(-1), with a detection limit of 37.2 nmol L(-1) and RSD of 4.7 % (n = 7). Approximately 12 % of the total amount of TNT was captured. The proposed methods are well-suited to trace detection and capture of TNT in aqueous solution.


A study of [D-Pro2, D-Phe7, D-Trp9]-substance P and [D-Trp7,9]-substance P as tachykinin partial agonists in the rat colon.
Two substance P (SP) analogues, [D-Pro2, D-Phe7, D-Trp9]-SP (DPDPDT) and [D-Trp7,9]-SP (DT79), previously described as tachykinin antagonists, have been shown to contract the rat colon muscularis mucosae preparation. The maximum response exhibited by these analogues was about 30% that of the SP maximum, suggesting that they were acting as partial agonists relative to SP. The responses to DPDPDT were unaffected by pretreatment with mepyramine, methysergide or [Sar1, Ile5, Ala8]-angiotensin II, which abolished the responses to histamine, 5-hydroxytryptamine (5-HT) and angiotensin II, respectively. Methysergide also did not affect the responses to DT79; the other antagonists were not tested against this analogue. Indomethacin and cimetidine also had no inhibitory effect. Atropine (2 microM) was present in all experiments to prevent indirect muscarinic effects. Phenoxybenzamine did not affect the dose-response curves to SP, eledoisin-related peptide (ERP), kassinin, eledoisin or physalaemin, nor did it affect the responses to individual doses of DPDPDT or DT79. However, in the absence of atropine, it shifted the carbachol dose-response curve markedly to the right, and reduced its maximum. The tachykinin antagonist [D-Pro4, D-Trp7,9,10]-SP4-11 reduced the responses to individual matched doses of DPDPDT, DT79 and SP to the same degree, whilst leaving responses to 5-HT or angiotensin II unaffected. This suggested that DPDPDT and DT79 were acting at the same receptor as SP. The inhibitory effects of DPDPDT on responses to SP, ERP and kassinin, and that of DT79 on responses to SP, were analysed. All four combinations yielded data compatible with an interaction at only one receptor, although DPDPDT appeared slightly more potent at inhibiting responses to kassinin. The results are discussed in the light of the proposed existence of multiple tachykinin receptor subtypes. The possible influence of differential metabolism of tachykinin analogues is also considered.


Use of psychotropic drugs in 0 to 5 years old children in Aquitaine (France): prevalence and associated factors.
To describe the use of psychotropic drugs in children aged 0-5 years, in the Aquitaine region of South-west France and identify associated socio-demographic, familial and medical factors. Data used in this study come from the regional drug claims database of the National Health Insurance System of Aquitaine and from postal self-questionnaires sent to parents and prescribing physicians. In Aquitaine, psychotropic drugs were redeemed at least once in 2002 for 3.2% of young children. Hydroxyzine, niaprazide or diazepam were claimed at least once by 2.7% of children registered in the database. Prescribers were mostly general practitioners (76.7%) and pediatricians (20.1%). Psychotropic claims were more frequent in children having the highest number of medical consultations in 2002 (more than 7: odds ratio (OR) = 1.5 [95% confidence interval (CI): 1.3-1.7]) or of drug deliveries (7-15 deliveries: OR = 1.8 [95%CI: 1.6-2.1]; more than 15 deliveries: OR = 3.2 [95%CI: 2.7-3.9]). Psychotropic claim frequency increased with age. No association of psychotropic use with parental psychotropic use, socio-professional category and familial situation was found. Psychotropic delivery prevalence in Aquitaine in young children was below 5% in 2002. It notably concerned drugs of which the use is not devoid of toxicity because of anticholinergic properties.


Swainsonine-induced vacuolar degeneration is regulated by mTOR-mediated autophagy in HT22 cells.
The indolizidine alkaloid, swainsonine (SW), is the main toxic component of locoweed, which can cause locoism in animals with characteristic neurological dysfunction. Pathological manifestations at cellular level include extensive vacuolar degeneration. Studies have shown that SW can induces autophagy, but the role and mechanism of autophagy in SW-induced vacuolar degeneration is unclear. In this study, we analyzed the role of autophagy in SW-induced cell injury in mouse hippocampal neurons cell line (HT22) using western blotting, qRT-PCR, transmission electron microscopy and immunofluorescence microscopy. The results showed that the expressions of LC3-II, ATG5, Beclin1 and p62 proteins and their mRNAs in HT22 cells were induced by SW treatment. The SW treatment increased the number of autophagosomes with enhanced fluorescence intensity of monodansylcadaverine (MDC) and LC3-II in a time-dose dependent manner. The results of lysosome staining showed that SW could increase the number of lysosomes, increase the intraluminal pH. Transmission electron microscopy results indicate that SW induced autophagosomes, and Baf A1 could effectively alleviate SW-induced vacuolar degeneration. At the molecular level, SW treatment inhibited the expression of p-PI3K, p-AKT, p-ERK, p-AMPK, p-mTOR, p-p70S6K and p-4EBP1 and promoted the expression of p53. Our results collectively suggest, PI3K/AKT/mTOR, ERK/mTOR and p53/mTOR signaling pathways are involved in the regulation of SW-induced autophagy in HT22 cells, while the AMPK/mTOR signaling pathway is not involved in this regulation. Inhibition of autophagic degradation can effectively alleviate SW-induced vacuolar degeneration.


Errors in the assessment of the efficacy of MRI pulse sequences.
The effects of the echo delay TE on contrast in saturation recovery MRI have been analyzed both theoretically and with experimental brain scans. It is demonstrated that the influence of the TE values offered as minimal values by all major current equipment manufacturers is not insignificant, but produces a degree of T2 weighting that considerably degrades the useful contrast that could be obtained from T1 weighted studies. Consequently, conclusions drawn about the relative performances of T1 and T2 weighted sequences may be incorrect if based on saturation recovery images obtained with inappropriate echo times.


[Study on out-of-pocket expenditure and related factors among cancer inpatients with Hunan Provincial Urban Employee Basic Medical Insurance].
To explore the level and influential factors for out-of-pocket (OOP) expenditure regarding Hunan Provincial Urban Employee Basic Medical Insurance (UEBMI) and to provide evidence for improvement of medical insurance payment system. Stratified random sampling method was used to obtain 10 527 records of cancer inpatients from January 2011 to December 2014. Social demographic and expenditure information were collected from UEBMI information system. The proportion of OOP expenditure for inpatient and each part of the cost was described. Multiple linear regression was used to analyze main related factors of OOP expenditure. The median proportion of OOP for inpatients costs was 20.11%, and remained stable from 2011 to 2014. The main related factors for OOP expenditure were age, civil servant, retirment status, hospital level, cost of hospitalization, hospitalization duration, medicine cost, proportion of general medical service charges, treatment cost, expenses of examination and laboratory test, and cancer type. OOP expenditure among UEBMI cancer inpatients was under control and stable. The level can well reflect the policy preferences. It could be further improved through the control of related factors, particularly the hospital level.


Long term preliminary studies on toxic and carcinogenic effect of individual or simultaneous exposure to ochratoxin A and penicillic acid in mice.
Carcinogenic effects of ochratoxin A (OTA) on liver, kidneys, intestine, muscles and subcutaneous tissue of BALB/c albino mice divided in three experimental and one control groups (30 mice in each group - 15 males and 15 females) and exposed to 10 ppm OTA and/or 50-60 ppm penicillic acid (PA) in the diet were seen. A total 22 neoplasias were found to be induced in the mice during 20 months' experimental period. Among them 14 were malignant and 8 benign. The number of neoplasias was significantly higher in the mice treated simultaneously with OTA and PA (14) compared to those in mice treated with OTA only (8). The number of malignant neoplasias was also higher (14) compared to benign neoplasias (8). Nine of a total fourteen malignant neoplasis and five of a total eight benign neoplasias were seen in the male mice. Pathological changes in mice after two weeks' experimental period were characterized by degenerative changes in kidneys, liver and gastrointestinal tract, which were better expressed in the mice exposed simultaneously to OTA and PA. A strong synergistic effect was found between OTA and PA towards tumorogenesis. It seems that mice are not a good experimental model for humans with regard to OTA-induced tumourigenesis, because the target organ of OTA-toxicity in humans or pigs is mainly the kidney, but not the liver, intestines, subcutaneous tissue or muscles as seen in this study.


Autoradiographic demonstration of the distribution of vagal afferent nerve fibers in the epiglottis of the rabbit.
After injection of [3H]leucine into the nodose ganglion of a rabbit autoradiographic examination of the distribution of vagal afferent fibers in the epiglottal wall revealed many nerve bundles of labeled afferent fibers present in the submucosal plexus between the cartilage tissue and the mucosa. The labeled afferent fibers, most of which were myelinated (while a few were unmyelinated), descended towards the mucosa, and then appeared to demyelinate at the subepithelial layer of the mucosa. The labeled afferent fibers entered the mucosal epithelium, terminated as free endings in the intercellular space among the epithelial cells, and extended near the mucosal surface. Grains were also observed near the taste buds in the epithelium, which suggests that some vagal afferent fibers innervated the epiglottal taste buds.


Pharmacological properties of fucose. Applications in age-related modifications of connective tissues.
Fucose is the only component of glycoconjugates of vertebrates in the L-configuration. It exhibits a number of unique and interesting biological properties reviewed briefly in this article. Its constant end-standing position on glycan chains predisposes fucose to play a key role in cell-cell and cell-matrix interactions, mediated by several receptors such as those recognising the Lewis-type blood group substances, fucose-recognising lectines and the mannose-fucose receptors. Some of the as yet unstudied or less well understood properties of L-fucose were explored in the present study, as its non-enzymatic interaction with amine-groups on macromolecules, its cellular uptake attributed to specific transport mechanisms and its effect on fibroblast cell cultures. We could document the stimulation of cell-proliferation and the inhibition of MMP-expression and activation, both for MMP-2 and MMP-9. These and the other shortly reviewed properties of L-fucose may play an important role in its biological applications and actions.


The effects of propolis on pro-oxidant-antioxidant balance, glycemic control, and quality of life in chronic kidney disease: a randomized, double-blind, placebo-controlled trial.
Chronic kidney disease (CKD) is a progressive kidney damage with an increasing prevalence. Some evidence suggests that propolis as a novel antioxidant, anti-inflammatory, and immunomodulatory agent may have beneficial effects in CKD. The aim of this study was to evaluate the efficacy of propolis on some kidney function parameters, pro-oxidant-antioxidant balance (PAB), glycemic status, quality of life, and blood pressure (BP) in patients with CKD. In this study, 44 patients with CKD were randomly assigned to receive propolis capsules at a dose of 250 mg daily or placebo for three months. Of 44 randomized individuals, 35 completed the trial. At the end of the intervention (end of month three), improvement in some dimensions of health-related quality of life (HRQoL) (derived from Kidney Disease and Quality of Life Short-Form (KDQOL-[Formula: see text], v. 1.3) questionnaire) were significantly higher in the propolis group than the placebo group, even after adjustment for baseline values, present of diabetes, and age (P < 0.05). Like systolic and diastolic BP, changes in serum creatinine, 24-h urine volume and protein, fasting blood sugar (FBS), hemoglobin A1C (HbA1C), insulin, homeostasis model of assessment-insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and PAB did not differ significantly between the two groups (P > 0.05). No serious adverse events were reported throughout the study. Propolis supplementation may improve the HRQoL of CKD patients. More studies are needed to validate the adjunct use of propolis for metabolic control of CKD patients.


Effects of SLC45A2 and GPNMB on Melanin Deposition Based on Transcriptome Sequencing in Chicken Feather Follicles.
As an essential genetic and economic trait, chicken feather color has long been an important research topic. To further understand the mechanism of melanin deposition associated with coloration in chicken feathers, we selected feather follicle tissues from the neck and wings of chickens with differently colored feathers (yellow, sub-Columbian, and silver) for transcriptome analysis. We focused on genes that were expressed in both the wings and neck and were expressed with the same trends in breeds with two different plumage colors, specifically, SLC45A2, GPNMB, MLPH, TYR, KIT, WNT11, and FZD1. GO and KEGG enrichment analyses showed the DEGs were enriched in melanin-related pathways, such as tyrosine metabolic pathway and melanogenesis, and PPI analysis highlighted the genes SLC45A2 and GPNMB as associated with melanin deposition. Verification experiments in chicken melanocytes demonstrated that these two genes promote melanocyte melanin deposition. These data enrich our knowledge of the mechanisms that regulate chicken feather color.


[Interaction of Escherichia coli RNA-polymerase with DNA-duplexes containing repetitive sequences].
Nitrocellulose filter binding technique has been used to study the binding of E. coli RNA polymerase to synthetic DNA duplexes (100-200 base pairs), containing the repeating fragments of promoters. It has been shown, that the duplex, containing the repeats of "ideal". Pribnow box forms heparin resistant complexes with enzyme, the stability of which is comparable with that of lacUV5 promoter complexes (the half life is approximately 200 min). The synthetic polynucleotide with repeating trp-promoter-operator sequence less stable complexes with RNA polymerase, the half life of which being 30 min.


Enzyme replacement via liposomes. Variations in lipid compositions determine liposomal integrity in biological fluids.
Liposomes survive exposure to biological fluids poorly, extruding trapped enzymes, drugs, or solutes upon interaction with serum or plasma constituents. We have quantified the disruptive effects of human serum on liposomes and have studied whether various modifications in their phospholipid composition might produce liposomes with an increased carrier potential for application in vivo. Multilamellar liposomes (phosphatidycholine 70:dicetyl phosphate 20:cholesterol 10) were prepared with 3H-labeled phosphatidylcholine as the lipid phase marker and [14C]inulin and horseradish peroxidase as aqueous phase markers. Gel exclusion chromatography showed that 32 +/- 3% of [14C]inulin and 27 +/- 7% of horseradish peroxidase were lost after 1 h incubation with 10% (v/v) human serum. Loss of aqueous solutes was reduced to 20 +/- 5%/h and 17 +/- 2%/h, respectively, after treatment with decomplemented serum (56 degrees C, 30 min). Loss induced by serum was concentration and time dependent: to 57 +/- 2% at 1 h and 67 +/- 14% at 24 h, with 50% serum; plasma was slightly less perturbing whereas human serum albumin was not at all disruptive. By incorporating sphingomyelin (35 mol%) into multilamellar liposomes, the leakage of [14c]-inulin in the presence of 10% serum was reduced to 12 +/- 4%/h; increasing the molar percentage of cholesterol to 35% also stabilized the lipid bilayers, reducing leakage to 20 +/- 7%/h. Both small and large unilamellar vesicles could not be stablilized against serum-mediated leakage by the incorporation of sphingomyelin. The data suggest that cholesterol and sphingomyelin enhance liposomal integrity in the presence of serum or plasma and promise to yield enhanced survival of drug-laden lipid vesicles in biological fluids in vivo.


Effect of cis-dichlorodiammine platinum(II) on the agglutinability of tumor and normal cells with concanavalin A and wheat germ agglutinin.
In this paper we report the effect of cis-dichlorodiammine platinum(II) (cis-platin) on the agglutination of normal and transformed lymphocytes with lectins conconavalin A (Con A) and wheat germ agglutinin (WGA) which is a sensitive test to study the expression of cell surface components. Normal splenocytes showed small degree of cell agglutination with Con A and WGA. This cell agglutination of normal splenocytes with these lectins increases significantly after cis-platin treatment at 37 degrees C. The Dalton's lymphoma cells which show a high degree of cell agglutination with Con A and WGA when treated with cis-platin at 37 degrees C results in decrease in the degree of their cell agglutination with these lectins. Agglutination inhibition studies with alpha-methyl-D-glucopyranoside for Con A and N-acetyl-D-glucosamine for WGA shows that this increase and decrease of cell agglutination after platinum treatment of cells is a specific reaction and not non-specific. Incubation of cis-platin treated normal splenocytes with excess of neuraminic acid results in decrease of cell agglutination with both Con A and WGA. cis-Platin treatment of the cells results in the release of sialic acid from the surface of the cells. A correlation between the release of sialic acid from the cell surface and cell agglutination is also discussed.


Glomerular filtration effects of acute volume expansion: importance of chloride.
The present studies were done to determine the effect on GFR of acute volume expansion (AVE) using solutions of various sodium salts and to explore if degree of tubuloglomerular feedback (TGF) activation plays a role in any GFR differences. Free-flow micropuncture and inulin clearance studies were combined to investigate anesthetized Munich-Wistar rats expanded to 10% body weight with isotonic solutions of NaCl, Ringers bicarbonate (RB), NaHCO3, Na acetate (NaAc) and Na2SO4 as well as euvolemic controls. In the clearance studies, AVE yielded per gram kidney weight GFR's greater than control (1009 +/- 51 microliter/min) in the NaCl and RB (chloride expanded) groups (1397 +/- 89 and 1389 +/- 64) microliter/min, respectively, P less than 0.05 vs. control) but not in the NaHCO3, NaAc, and Na2SO4 (non-chloride expanded) groups. Proximal minus distal single nephron GFR determinations (P-D), an estimate of the degree of TGF, were less than control 13.2 +/- 2.1 nl/min) in the NaCl and RB groups (4.1 +/- 0.7 and 5.3 +/- 1.9 nl/min, respectively, P less than 0.05 vs. control) but were not significantly different from control in any of the non-chloride expanded groups. Early distal (ED) fluid flow correlated positively with P-D in all groups. ED chloride concentration but not TCO2 nor osmolality correlated with P-D for all groups. The correlation was negative for control and chloride expanded groups and positive for non-chloride expanded groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration.
Hyperinsulinemia/insulin resistance and elevated plasma free fatty acids (FFA) levels are involved in the hypertension and cardiac sympathetic overactivity. Metformin improves insulin action and lower plasma FFA concentrations. We investigate the possible effect of metformin on arterial blood pressure (BP) and cardiac sympathetic nervous system. One hundred twenty overweight type 2 diabetic patients were treated by placebo (n = 60) + diet or metformin (850 mg twice daily) (n = 60) + diet for 4 months, to evaluate the effect of metformin treatment on the cardiac autonomic nervous system. Insulin resistance was measured by the Homeostasis Model Assessment (HOMA) index. Heart rate variability (HRV) assessed cardiac sympathovagal balance. Metformin treatment, but not placebo treatment, was associated with a decrease in fasting plasma glucose (P <.05), insulin (P <.05), triglyceride (P <.05), and FFA (P <.03) concentrations and HOMA index (P <.03). Metformin treatment was also associated with a significant improvement in cardiac sympathovagal balance but not in mean arterial BP. Furthermore, in a multivariate analysis, delta change in sympathovagal balance index (LF/HF ratio) were associated with delta change in plasma FFA concentrations and HOMA index independently of gender and delta change in plasma triglyceride and HbA1c concentrations. Our study demonstrated that metformin treatment might be useful for improving cardiac sympathovagal balance in obese type 2 diabetic patients.


Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein.
The human ra1 proteins share more than 50% homology and some properties with the ras proteins. The RALB gene, a new member of the ra1 family, has been isolated, sequenced, and assigned to human chromosome 2 cen-q13. One other member of this family, RALA, has been previously mapped to the short arm of human chromosome 7.


Predictors of 30-day morbidity and mortality in transnasal microscopic pituitary tumor excision.
There is a lack of population-based, multi-institutional analyses of factors associated with morbidity and mortality following pituitary tumor excision. The American College of Surgeons National Surgical Quality Improvement Project files were used to compile information on patients that had undergone transnasal microscopic pituitary tumor resection from 2006 to 2012. Patient demographics, comorbidities, operative characteristics, and morbidity and mortality in the 30 days following surgery were included. Multivariate logistic regression was used for categorical variables and multivariate linear regression was used for continuous variables to evaluate factors leading to adverse events. A total of 658 patients were included, of which 58 (8.81%) experienced a complication, reoperation or death in the 30 days following surgery. The most common complications were reoperation (3.37%), followed by unplanned reintubation (1.99%), urinary tract infection (1.68%), and transfusion (1.68%). Predictors of any complication, reoperation, or death include preoperative sepsis (odds ratio [OR] = 7.596) and lower preoperative serum albumin (OR = 6.667). Younger age predicted surgical complications (OR = 1.105). Predictors of medical complications include higher body mass index (OR = 1.112), chronic steroid use (OR = 6.568), preoperative sepsis (OR = 15.297), and lower preoperative serum hematocrit (OR = 1.225). Predictors of increased total length of hospital stay were older age (β = 0.146), higher body mass index (β = 0.188), chronic steroid use (β = 0.142), preoperative sepsis (β = 0.489), and lower preoperative serum albumin (β = -0.213). Although adverse events following pituitary tumor excision are low, awareness of factors associated with morbidity and mortality in the early postoperative period may allow for improved patient monitoring and outcomes.


Repetitive domestication to enhance butanol tolerance and production in Clostridium acetobutylicum through artificial simulation of bio-evolution.
To improve butanol tolerance and production in Clostridium acetobutylicum, a novel approach was developed in this study, which was called artificial simulation of bio-evolution (ASBE) based on the evolutionary dynamics and natural selection. Through repetitive evolutionary domestications, a butanol-tolerant strain C. acetobutylicum T64 was obtained, which could withstand 4% (v/v) (compared to 2% of the wild-type) butanol and was accompanied by the increase of butanol production from 12.2g/L to 15.3g/L using corn meal as substrate. Fermentation was also carried out to investigate the relationship between butanol tolerance and ABE production, suggesting that enhancing butanol tolerance could increase butanol production but unlikely improve total ABE production. These results also indicated that the ASBE would be an available and feasible method used in biotechnology for enhancement of butanol tolerance and production.


[B lymphocytes and plasma cells as drivers of rheumatic diseases].
Various research groups at the German Rheumatism Research Center in Berlin, in close cooperation with the Department of Rheumatology and Clinical Immunology of the Medical Clinic at the Charité, have made important contributions to the significance of B cells and plasma cells in rheumatic diseases, which are relevant not only for rheumatology but for all clinical specialties in which antibody-mediated diseases play a role. In particular, the research addresses impaired B cell homeostasis, the importance of the IgM Fc receptor in the regulation of autoimmunity, the role of long-lived memory plasma cells in maintaining autoimmunity and ensuring its survival in specific niches organized by stromal cells in bone marrow and inflamed tissues. The research results have contributed to a better understanding of the immunological and molecular mechanisms in rheumatic diseases and their treatment. The identification of the long-lived memory plasma cell has led to promising treatment approaches with curative potential in autoimmune diseases.


The association between the inflammatory potential of diet and the risk of histopathological and molecular subtypes of breast cancer in northwestern Iran: Results from the Breast Cancer Risk and Lifestyle study.
This study explored the association between diet-associated inflammation and the risk of different molecular subtypes of breast cancer (BrCA) in a large, population-based case-control study conducted in northwestern Iran. The study consisted of 1007 women with histopathologically confirmed BrCA and 1004 controls admitted to hospitals in Tabriz, northwestern Iran, for nonneoplastic conditions. Dietary Inflammatory Index scores and energy-adjusted Dietary Inflammatory Index (E-DII) scores, with and without supplements, were computed on the basis of dietary intake collected using a validated 136-item food frequency questionnaire. Women with the highest E-DII scores (quartile 4) versus those with the lowest E-DII scores (quartile 1) showed a significantly increased BrCA risk (odds ratio for quartile 4 vs quartile 1 [ORQ4vsQ1 ], 1.87; 95% confidence interval [CI], 1.42-2.47), particularly for lobular carcinoma (ORQ4vsQ1 , 3.07; 95% CI, 1.34-7.02). Findings were similar for premenopausal women diagnosed with luminal A BrCA (ORQ4vsQ1 , 2.71; 95% CI, 1.74-4.22) or luminal B BrCA (ORQ4vsQ1 , 2.86; 95% CI, 1.39-5.89). Women consuming the most proinflammatory diets were 3 times more likely to have triple-negative BrCA (ORQ4vsQ1 , 3.00; 95% CI, 1.002-8.96) while compared to luminal A BrCA. The BrCA risk for women consuming diets in the highest half of E-DII scores (E-DII > 0) was 59% greater than the risk for those in the lowest half (95% CI, 1.29-1.97). Also, higher E-DII scores that took into account supplements were associated with larger tumor sizes (T3 > 5 cm; P < .05). A proinflammatory diet, as indicated by higher E-DII scores, appears to increase the risk of BrCA in Iranian women. Large increases in risk were seen in invasive molecular subtypes of BrCA. Anti-inflammatory diets are suggested to prevent the risk of overall BrCA and more aggressive forms of BrCA in particular.


Studies on the binding of 1-anilino-8-naphthalene sulfonate to very low density and high density himan serum lipoproteins.
Very low density and high density lipoproteins have been isolated from human plasma and their interaction with 1-anilin0-8-naphthalene sulfonate has been studied under different conditions of pH and added salt. Intrinsic fluorescence of bound 1-anilino-8-naphthalene sulfonate was higher for high density lipoproteins then for very low density lipoproteins, but was unaffected by salt in both systems. Binding of 1-anilino-8-naphthalene sulfonate by both these lipoproteins was saturable and was higher in the presence of added NaCl or CaCl2, Ca2+ having a greater effect than Na+ in enhancing fluorescence. The binding data were analyzed by Scatchard plots; the number of binding sites and the affinity of 1-anilino-8-naphthalene sulfonate for the site increased with increasing salt concentration. Fluorescence pH curves were similar to those published for phospholipids. From these and previous observations it is suggested that the phospholipids probably represent the major binding sites for 1-anilino-8-naphthalene sulfonate.


Violence prevention and young adolescents' participation in community youth service.
To examine whether participation in a school-sponsored community youth service program reduces self-reported violent behaviors among young urban adolescents. A total of 972 seventh- and eighth-grade students at two large, urban, public middle schools were surveyed at baseline and at 6-month follow-up. One school was assigned to interventions and the other served as a control. All students at the intervention school received the Reach for Health classroom curriculum that included a 10-lesson unit focusing on violence prevention. In addition, approximately half the students were randomly assigned by classroom to participate in the Reach for Health Community Youth Service program (CYS). Under the guidance of teachers and community nurses, these students spent several hours each week providing service in local health care agencies. Regression analyses were used to assess the influence of treatment condition on violent behavior outcomes. Comparing students in the curriculum-only and curriculum-plus-CYS interventions to the control group, there is a statistically significant interaction (p < .03) among grade, CYS participation, and violence at follow-up. Eighth-grade CYS students reported significantly less violence at follow-up than students in the control school, taking into account baseline level of risk behavior, gender, ethnicity, and social desirability (p < .04). There was no significant difference between controls and students in the curriculum-only condition. Comparing students in the CYS intervention to the curriculum-only condition within the intervention school, the grade by intervention interaction again is significant (p < .05). Eighth-grade CYS students-who received the broadest CYS experience-reported less violence at follow-up than their curriculum-only counterparts. When delivered with sufficient intensity, school programs which couple community service with classroom health instruction can have a measurable impact on violent behaviors of a population of young adolescents at high risk for being both the perpetrators and victims of peer violence. Community service programs may be an effective supplement to curricular interventions and a valuable part of multicomponent violence prevention programs.


Assessment of the antiulcer potential of Moringa oleifera root-bark extract in rats.
In the present study, an ethanolic root-bark extract of Moringa oleifera (MO) was examined for its antiulcer potential in albino Wistar rats using two experimental models: ethanol-induced and pylorus ligation-induced gastric ulceration. The extract was orally administered at three different doses (150, 350, and 500 mg/kg) for 15 consecutive days. The antiulcer effects in rats treated with different doses of the extract and omeprazole (30 mg/kg, p.o.) were determined and compared statistically with the antiulcer effects in the control rats treated with saline (NaCl, 0.9%). The MO at doses of 350 and 500 mg/kg decreased the ulcer index significantly as compared to the control group (p < 0.01). The percentage protections against gastric ulcers were 82.58%, 85.13%, and 86.15% for MO doses of 150, 350, and 500 mg/kg, respectively, in the pylorus-ligated ulcer model and 55.75%, 59.33%, and 78.51%, respectively, in the ethanol-induced ulcer model. The MO significantly reduced the free acidity, total acidity, and ulcer index (p < 0.01) and increased the pH of gastric content compared with the control group. This study suggests that MO possesses valuable antiulcer, antisecretory, and cytoprotective activity. Thus, an ethanolic root-bark extract of Moringa oleifera can be used as source for an antiulcer drug.


Hydroxynaphthoquinone metal complexes as antitumor agents x: synthesis, structure, spectroscopy and in vitro antitumor activity of 3-methyl-phenylazo lawsone derivatives and their metal complexes against human breast cancer cell line mcf-7.
The C-3 substituted phenylazo derivatives of lawsone (2-hydroxy-l,4 p-naphthoquinone, III) were synthesized and characterized. The X-ray crystal structure was determined for the ligand 3-(3'-methyl phenylazo) lawsone. The copper complexes of these derivatives were found to possess 1:2 metal stoichiometry and square planar geometries with intermolecular stackings, resulting in antiferromagnetic exchange interactions. The in vitro activity of all the synthesized compounds was examined against human breast cancer cell-line, MCF-7, which revealed enhanced activities for the metal complexes, the highest activity being observed for the copper compound of 3-(3'-methyl phenylazo) lawsone.


A gamete-specific, sex-limited homeodomain protein in Chlamydomonas.
During fertilization in Chlamydomonas, gametes of opposite mating types interact with each other through sex-specific adhesion molecules on their flagellar surfaces. Flagellar adhesion brings the cell bodies of the gametes into close contact and initiates a signal transduction pathway in preparation for cell-cell fusion. We have identified a cDNA, gsp1, whose transcript levels are upregulated during flagellar adhesion. The GSP1 polypeptide is a novel, gamete-specific homeodomain protein, the first to be identified in an alga. Its homeodomain shows significant identity with several higher plant homeodomain proteins. Although encoded by a single copy gene present in cells of both mating types, immunoblot analysis showed that GSP1 was expressed in mating type (mt)+ gametes, but was not detectable in mt- gametes or in vegetative cells of either mating type. Moreover, GSP1 appeared late during gametogenesis, suggesting that it may function during adhesion with mt- gametes or after zygote formation. GSP1 is expressed in imp11, mt- mutant gametes, which have a lesion in the mid gene involved in sex determination and exhibit many phenotypic characteristics of mt+ gametes. Thus, gsp1 is negatively regulated by mid and is the first molecule to be identified in Chlamydomonas that shows sex-limited expression.


Transcatheter closure of a ruptured ventricular septum after myocardial infarction using a venous approach.
A 65-year old patient was admitted after having sustained a ventricular septum rupture 18 days after an anterior myocardial infarction. He developed acute heart failure. Given the extremely high perioperative risk in surgical approaches in this setting, we decided for a transcatheter closure of the defect with an exclusively venous approach. After a complete recovery, the patient underwent open heart surgery with aorto coronary bypass, aneurysmectomy, and removal of the closure device. This case demonstrates that transcatheter closure of a post infarction ventricular septum rupture is a technically feasible and suitable method.


Multiplexed protein stability (MPS) profiling of terminal degrons using fluorescent timer libraries in Saccharomyces cerevisiae.
N-terminal protein sequences and their proteolytic processing and modifications influence the stability and turnover of proteins by creating potential degrons for cellular proteolytic pathways. Understanding the impact of genetic perturbations of components affecting the processing of protein N-termini and thereby their stability, requires methods compatible with proteome-wide studies of many N-termini simultaneously. Tandem fluorescent timers (tFT) allow the in vivo measurement of protein turnover completely independent of protein abundance and can be deployed for proteome-wide studies. Here we present a protocol for Multiplexed Protein Stability (MPS) profiling of tFT-libraries encoding large numbers of different protein N-termini fused to tFT in the yeast Saccharomyces cerevisiae. This protocol includes fluorescence cell sorting based profiling of these libraries using a pooling approach. Analysis of the sorted pools is done by using multiplexed deep sequencing, in order to generate a stability index for each N-terminally peptide fused to the tFT reporter, and to evaluate half-life changes across all species represented in the library.


Management of sepsis following injury.
Sepsis is a significant cause of late morbidity and mortality in the severely injured patient. In addition to the risk factors of shock, multiple transfusions, and contamination, the trauma patient may have the additional factor of severe immunologic depression. The prevention of sepsis should be an early consideration. Invasive diagnostic and therapeutic maneuvers should be limited to those that are absolutely necessary, since the incidence of nosocomial infection is high. Prophylactic antibiotics should not be misused, as these may increase the risk of serious, resistant infections. Frequent examination of sputum smears may allow the early diagnosis of pneumonia. Nutritional supplementation can improve host defenses, and should be instituted early. The patient in septic shock should be resuscitated and stabilized in the intensive care unit. Monitoring should include determination of cardiac index and systemic oxygen consumption. Computed tomography has emerged as the primary modality for the diagnosis of intra-abdominal sepsis. When combined with percutaneous drainage of abscesses, it represents a rapid and safe approach to the diagnosis and treatment of the critically ill septic patient. In certain cases, such as bowel perforation or necrosis, anastomotic breakdown, or acalculous cholecystitis, laparotomy is the procedure of choice. Opportunistic infections may become significant in patients who have required a prolonged course of treatment. In the patient with multiple organ-system failure who is not responding to therapy and in whom no clear source of sepsis has been identified, exploratory laparotomy should be considered. Antibiotics should be used with caution and should not started in every patient with a fever. Their use should be directed by appropriate cultures and sensitivities.(ABSTRACT TRUNCATED AT 250 WORDS)


Psychometric qualities of a tetrad WAIS-III short form for use in individuals with mild to borderline intellectual disability.
To investigate the reliability and validity of a Wechsler Abbreviated Scale of Intelligence-based Wechsler Adult Intelligence Scale - third edition (WAIS-III) short form (SF) in a sample of individuals with mild to borderline intellectual disability (MBID) (N = 117; M(IQ) = 71.34; SD(IQ) = 8.00, range: 52-85). A full WAIS-III was administered as a standard procedure in the diagnostic process. The results indicate an excellent reliability (r = 0.96) and a strong, positive correlation with the full WAIS-III (r = 0.89). The SF correctly identified ID in general and the correct IQ category more specifically in the majority of cases (97.4% and 86.3% of cases, respectively). In addition, 82.1% of the full scale IQ (FSIQ) estimates fell within the 95% confidence interval of the original score. We conclude that the SF is a reliable and valid measure to estimate FSIQ. It can be used in clinical and research settings when global estimates of intelligence are sufficient.


Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus.
Detection of cytosolic DNA is a central element of the innate immunity system against viral infection. The Ku heterodimer, a component of the NHEJ pathway of DNA repair in the nucleus, functions as DNA sensor that detects dsDNA of viruses that replicate in the cytoplasm. Vaccinia virus expresses two proteins, C4 and C16, that inactivate DNA sensing and enhance virulence. The structural basis for this is unknown. Here we determine the structure of the C16 - Ku complex using cryoEM. Ku binds dsDNA by a preformed ring but C16 sterically blocks this access route, abrogating binding to a dsDNA end and its insertion into DNA-PK, thereby averting signalling into the downstream innate immunity system. C4 replicates these activities using a domain with 54% identity to C16. Our results reveal how vaccinia virus subverts the capacity of Ku to recognize viral DNA.


Alternative modification by grafting in bamboo cellulose nanofibrils: A potential option to improve compatibility and tunable surface energy in bionanocomposites.
Chemical modification in surface of cellulose nanofibrils CNFs (20 nm) from an endemic and non-significant value-added, Argentine bamboo, was developed. The modification in the CNFs was carried out with three simple routes using a low molecular weight polylactic acid synthesized in our laboratory (PLA1). The first step comprises of protection of the hydroxyl groups of PLA1 through a benzoylation (PLA1Bz). The next step consisted of the activation of carboxyl groups using thionyl chloride and the last reaction was the grafting of the modified PLA onto the CNFs (PLA1Bz-g-CNF). The covalently functionalization is confirmed by spectroscopically techniques as well as PLA1Bz-g-CNFs were characterized by thermal analyses. The PLA1Bz-g-CNFs were taken up such as nanocharges to improve properties of compatibilization and changing surface properties in films based on PLA. The comparison between the films with PLA1Bz-g-CNFs with respect to the physic mixture of the components (PLA1Bz/CNF), shows an improvement in the thermal, mechanical, and surface properties of the material, particularly when 5% of PLA1Bz-g-CNFs was added. The dispersive (γS D) component of film is increased in 36.1 mN/m respect to 29.3 mN/m from the films obtained with the physic mixture nanofibrils without modification and a plasticizing effect was noticed in the final material.


M-cholinoreactivity of erythrocytes of non-pregnant and pregnant women evaluated by changes in the rate of erythrocyte agglutination under the influence of acetylcholine.
Acetylcholine (5.5×10(-10)-5.5×10(-6)M) accelerated erythrocyte agglutination in men, non-pregnant women in follicular phase of the menstrual cycle, and pregnant women in the first trimester. The effect was blocked with atropine (5.5×10(-6)M). Acetylcholine had no effect on the rate of erythrocyte agglutination in non-pregnant women in the luteal phase and pregnant women in the second and third trimesters, which coincided with the development of myometrium refractoriness to acetylcholine in pregnant women. The results indicate that erythrocytes can reflect M-cholinoreactivity of internal organs.


Analysis of risk factors for postoperative complications in non-small cell lung cancer: comparison with the Japanese National Clinical Database risk calculator.
Although the risk calculator of the National Clinical Database (RC-NCD) has been widely used to predict the occurrence of mortality and major morbidity in Japan, it has not been demonstrated whether a correlation between the calculated RC-NCD risk score and the actual occurrence of mortality and severe morbidity exists. The clinical data of 585 patients who underwent pulmonary resection for non-small cell lung cancer were collected, and the risk factors for postoperative morbidity were analyzed to verify the validity of the RC-NCD. The coexistence of asthma (p = 0.02), nutrition lymphocyte ratio (p = 0.04), and pulmonary lobe (p < 0.01) were significant risk factors for postoperative morbidity in the present study, and the percent-predicted vital capacity (p < 0.01), pulmonary lobe (p = 0.03), and type of operative procedure (p = 0.01) were significant risk factors for severe postoperative morbidity. Furthermore, in patients received lobectomy, coexistence of asthma (p = 0.01) and pulmonary lobe (p < 0.01) were identified as significant risk factors for postoperative morbidity. Meanwhile, male sex (p = 0.01), high BMI (p < 0.01), low vital capacity (p = 0.04), and pulmonary lobe (p = 0.03) were identified as significant risk factors for severe postoperative morbidity. Given that the pulmonary lobe was a significant risk factor for postoperative morbidity in patients received pulmonary resection and for severe postoperative morbidity in patients received lobectomy, the RC-NCD for postoperative morbidity needs to be modified according to high-risk lobes. The Institutional Review Board of Kanazawa Medical University approved the protocol of this retrospective study (approval number: I392), and written informed consent was obtained from all patients.


Utilization of a radioiodinated bile salt for kinetic studies and hepatic scintigraphy. Studies in nonhuman mammals.
An 125I- or 131I-labeled bile salt derivative, cholylglycyliodohistamine, has been synthesized and purified. The bile salt derivative is rapidly cleared from the circulation when injected intravenously into rats and rabbits. Ten minutes after injection, approximately 50% of the recovered bile salt derivative was in the jejunum and ileum, and 36% was found in the liver. Sixty minutes after injection, 99% of the recovered radioactivity was found in the luminal gastrointestinal tract. The isotope was cleared from the circulation of rabbits with a t1/2 of approximately 2 min. Hepatic scintigraphy using rabbits demonstrated rapid uptake by the liver and excretion into the intestine. Quantitative analysis of scintigraphy showed an uptake rate of 14%/min and a subsequent excretory rate of 4.6/min.


Outcomes reported in randomised controlled trials of major depressive disorder in older adults: protocol for a methodological review.
Major depressive disorder (MDD or depression) is prevalent among adults aged 65 years and older. The effectiveness and safety of interventions used to treat depression is often assessed through randomised controlled trials (RCTs). However, heterogeneity in the selection, measurement and reporting of outcomes in RCTs renders comparisons between trial results, interpretability and generalisability of findings challenging. There is presently no core outcome set (COS) for use in RCTs that assess interventions for older adults with MDD. We will conduct a methodological review of the literature for outcomes reported in trials for adults 65 years and older with depression to assess the heterogeneity of outcome measures. RCTs evaluating pharmacotherapy, psychotherapy, or any other treatment intervention for older adults with MDD published in the last 10 years will be located using electronic database searches (MEDLINE, Embase, PsycINFO and the Cochrane Central Register of Controlled Trials). Reviewers will conduct title and abstract screening, full-text screening and data extraction of trials eligible for inclusion independently and in duplicate. Outcomes will be synthesised and mapped to core outcome-domain frameworks. We will summarise characteristics associated with trials and outcomes. We hope that findings from our methodological review will reduce variability in outcome selection, measurement and reporting and facilitate the development of a COS for older adults with MDD. Our review will also inform evidence synthesis efforts in identifying the best treatment practices for this clinical population. Ethics approval is not required, as this study is a literature review. CRD42021244753.


Microbiology of Acute and Chronic Osteomyelitis and Antibiotic Treatment.
Osteomyelitis is an inflammation of bone marrow with a tendency for progression, involving the cortical plates and often periosteal tissues, with most cases occurring after trauma to bone or bone surgery or secondary to vascular insufficiency. Antimicrobial therapy and surgical débridement are the primary modalities of osteomyelitis treatment, although often it is associated with a prolonged course, requiring a large commitment between patient and clinician as well as sizable health care costs. Despite surgical and chemotherapeutic advancements, osteomyelitis remains difficult to treat, and no universally accepted protocol for treatment exists.


Effects of cadmium on bioaccumulation and biochemical stress response in rice (Oryza sativa L.).
This study investigated the effects of various Cd concentrations on the bioaccumulation, antioxidative defense, and stress responses of rice (Oryza sativa L.). The distribution characteristics of Cd in rice were in the following order: roots>stems>grains. The bioconcentration factor values of Cd increased at concentrations lower than 3.00 mg Cd/kg and approximately decreased to a constant value at concentrations higher than 3.00 mg Cd/kg. Rice showed a higher Cd accumulation potential at low Cd concentrations than at high Cd concentrations. The Freundlich isotherm model described well the adsorption isotherms of Cd in rice roots. The biosorption mechanism of rice roots was determined to be cooperative adsorption. The malondialdehyde (MDA) content increased at a concentration range of 0.00-5.00 mg/L, indicating the enhancement of lipid peroxidation. By contrast, the MDA content slightly decreased at concentrations higher than 5.00 mg/L. Peroxidase (POD) activity exhibited active response to oxidative stress at concentrations lower than 5.00 mg/L but was inhibited at concentrations higher than 5.00 mg/L. The response to Cd stress of the N-H, O-H and C-O functional groups in rice shoots was observed via Fourier transform infrared spectroscopy.


Electrophile-induced cyclization/migration reaction for the synthesis of 2,3-dihydro-5-iodopyran-4-one.
A novel method for the construction of 2,3-dihydro-5-iodopyran-4-one through a domino cyclization/migration reaction of 1-alkynyl-2,3-epoxy alcohol was developed. Wet solvent is essential for this reaction. The resulting iodine-containing product can be readily elaborated to more complex products by using known organopalladium chemistry.


Mismatch repair protein loss in cutaneous head and neck squamous cell carcinoma.
The treatment of advanced cutaneous head and neck cutaneous squamous cell carcinomas (HNcSCC) results in significant morbidity. Recently, immune checkpoint inhibitor treatment has been approved for DNA mismatch repair (MMR) deficient patients in a histology-agnostic manner. This study aims to evaluate the incidence of MMR deficiency in advanced HNcSCC and its association with clinicopathologic factors. The cohort included 176 consecutive HNcSCC cases treated with curative intent. Immunohistochemistry for MMR proteins (hMLH1, hMSH2, hMSH6, and hPMS2) was performed. Clinicopathological and survival data was collected prospectively. The incidence of MMR protein deficiency was 9.1%. There was no association between age, incidence of metachronous malignancies, clinicopathological factors, or survival outcomes. A higher incidence of MMR deficiency was observed in this cohort of advanced HNcSCC. The lack of association with young age at onset or increased incidence of metachronous malignancies suggests that MMR deficiency is likely to be sporadic in HNcSCC.


Sedentary time and postmenopausal breast cancer incidence.
The objective of this study was to evaluate the prospective association between sedentary time and postmenopausal breast cancer incidence, and whether associations differ by race/ethnicity, physical activity levels, and body measurements. The Women's Health Initiative Observational Study is a prospective cohort among women ages 50-79 years at baseline (1994-1998) (analytic cohort = 70,233). Baseline questionnaire data were used to estimate time spent sitting and total sedentary time. Associations between time spent sitting and invasive breast cancer incidence overall (n = 4,115 cases through September 2015), and by hormone receptor subtypes, were investigated using Cox proportional hazards regression. Analyses were replicated stratified by race/ethnicity, body measurements, and physical activity. Among women in this study, 34.5% reported ≤ 5 h/day sitting, 40.9% reported 6-9 h/day and 24.7% reported ≥ 10 h/day. Time spent sitting (≥ 10 vs. ≤5 h/day adjusted HR = 1.00, 95% CI 0.92-1.09) was not associated with breast cancer incidence, regardless of hormone receptor subtype. Associations did not differ by race/ethnicity, physical activity, or body measurements. Results from this study do not support an association between sedentary time and breast cancer incidence.


Synchronized 2D/3D optical mapping for interactive exploration and real-time visualization of multi-function neurological images.
Efficient software with the ability to display multiple neurological image datasets simultaneously with full real-time interactivity is critical for brain disease diagnosis and image-guided planning. In this paper, we describe the creation and function of a new comprehensive software platform that integrates novel algorithms and functions for multiple medical image visualization, processing, and manipulation. We implement an opacity-adjustment algorithm to build 2D lookup tables for multiple slice image display and fusion, which achieves a better visual result than those of using VTK-based methods. We also develop a new real-time 2D and 3D data synchronization scheme for multi-function MR volume and slice image optical mapping and rendering simultaneously through using the same adjustment operation. All these methodologies are integrated into our software framework to provide users with an efficient tool for flexibly, intuitively, and rapidly exploring and analyzing the functional and anatomical MR neurological data. Finally, we validate our new techniques and software platform with visual analysis and task-specific user studies.


Neonatal immune signatures differ by sex regardless of neurodevelopmental disorder status: Macrophage migration inhibitory factor (MIF) alone reveals a sex by diagnosis interaction effect.
Immune dysregulation, including aberrant peripheral cytokine/chemokine levels, is implicated in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD). While the diagnosis of ASD is more common in males compared to females, sex effects in immune dysregulation related to neurodevelopment remain understudied. The aim of this exploratory study was to determine whether there are sex-specific effects in neonatal immune dysregulation with respect to an ASD or delayed development (DD) diagnosis. We utilized the data from the Early Markers for Autism study, a population based case-control study of prenatal and neonatal biomarkers of ASD. The immune profile of newborns later diagnosed with ASD (n = 482, 91 females), DD (n = 140, 61 females) and sex-matched general population controls (GP; n = 378, 67 females) were analyzed using neonatal bloodspots (NBS) via 42-plex multiplex assay. Multiple linear regression analysis was performed to identify whether sex was associated with differences in cytokine/chemokine levels of children with ASD, DD, and GP. A sex by diagnosis interaction effect was observed only for the chemokine macrophage migration inhibitory factor (MIF), with males displaying higher levels of NBS MIF than females in the GP control group (p = 0.02), but not in ASD (p = 0.52) or DD (p = 0.29) groups. We found that regardless of child diagnosis, newborn bloodspot eluates from females had a significantly higher concentration than males with the same diagnosis of the chemokines granulocyte chemotactic protein 2 (GCP-2; p < 0.0001), macrophage inflammatory protein 2-alpha (GROβ; p = 0.002), interferon-inducible t-cell alpha chemoattractant (I-TAC; p < 0.0001), stromal cell-derived factor 1 alpha and beta (SDF-1α-β; p = 0.03), innate inflammatory chemokines interferon-gamma induced protein 10 (IP-10; p = 0.02), macrophage inflammatory protein 1-alpha (MIP-1α; p = 0.02), and Th1-related pro-inflammatory cytokine interleukin-12 active heterodimer (IL-12p70; p = 0.002). In contrast, males had a higher concentration than females of secondary lymphoid-tissue chemokine (6CKINE; p = 0.02), monocyte chemotactic protein 1 (MCP-1; p = 0.005) and myeloid progenitor inhibitory factor 1 (MPIF-1; p = 0.03). Results were similar when analyses were restricted to NBS from DD and ASD further classified as ASD with intellectual disability (ID), ASD without ID, and DD (GCP-2, p = 0.007; I-TAC, p = 0.001; IP-10, p = 0.005; IL-12p70, p = 0.03 higher in females; MPIF-1, p = 0.03 higher in male). This study is the first to examine sex differences in neonatal cytokine/chemokine concentrations, and whether these differences are associated with neurodevelopmental outcomes. Results highlight the importance of considering sex as a critical factor in understanding the immune system as it relates to child development.


Renal tubular secretion of pramipexole.
The dopamine agonist pramipexole is cleared predominantly by the kidney with a major contribution of active renal secretion. Previously the organic cation transporter 2 (OCT2) was shown to be involved in the uptake of pramipexole by renal tubular cells, while the mechanism underlying efflux into tubular lumen remains unclear. Cimetidine, a potent inhibitor of multidrug and toxin extrusion proteins 1 (MATE1) and 2-K (MATE2-K), decreases renal pramipexole clearance in humans. We hypothesized that, in addition to OCT2, pramipexole may be a substrate of MATE-mediated transport. Pramipexole uptake was investigated using MDCK or HEK cells overexpressing OCT2, MATE1 or MATE2-K and the respective vector controls (Co). Transcellular pramipexole transport was investigated in MDCK cells single- or double-transfected with OCT2 and/or MATE1 and in Co cells, separating a basal from an apical compartment in a model for renal tubular secretion. Pramipexole uptake was 1.6-, 1.1-, or 1.6-folds in cells overexpressing OCT2, MATE1 or MATE2-K, respectively as compared to Co cells (p<0.05). In transcellular transport experiments, intracellular pramipexole accumulation was 1.7-folds in MDCK-OCT2 (p<0.001), and transcellular pramipexole transport was 2.2- and 4.0-folds in MDCK-MATE1 and MDCK-OCT2-MATE1 cells as compared to Co cells (p<0.001). Transcellular pramipexole transport was pH dependent and inhibited by cimetidine with IC50 values of 12μM and 5.5μM in MATE1 and OCT2-MATE1 cells, respectively. Taken together, coordinate activity of OCT2-mediated uptake and MATE-mediated efflux determines pramipexole renal secretion. Reduced OCT2 or MATE transport activity due to genetic variation or drug-drug interactions may affect pramipexole renal secretion.


A duplicated coxI gene is associated with cytoplasmic male sterility in an alloplasmic Brassica juncea line derived from somatic hybridization with Diplotaxis catholica.
A cytoplasmic male sterile (CMS) line of Brassica juncea was derived by repeated backcrossing of the somatic hybrid (Diplotaxis catholica + B. juncea) to B. juncea. The new CMS line is comparable to euplasmic lines for almost all characters, except for flowers which bear slender, needle-like anthers with aborted pollen. Detailed Southern analysis revealed two copies of coxI gene in the CMS line. One copy, coxI-1 is similar to the coxI gene of B. juncea, whereas the second copy, coxI-2 is present in a novel rearranged region. Northern analysis with eight mitochondrial gene probes showed altered transcript pattern only for the coxI gene. Two transcripts of 2.0 and 2.4 kb, respectively, were detected in the CMS line. The novel 2.4 kb transcript was present in floral bud tissue but absent in the leaf tissue. In plants where male sterility broke down under high temperature during the later part of the growing season, the 2.4 kb coxI transcript was absent, which suggested its association with the CMS. The two coxI genes from the CMS line showed two amino acid changes in the coding region. The novel coxI gene showed unique repeats in the 5' region suggesting recombination of mitochondrial genomes of the two species. The possible role of the duplicated coxI gene in causing male sterility is discussed.


Depressed spontaneous natural killing and interferon augmentation in patients with malignant lymphoma.
A substantial proportion (44%) of peripheral blood lymphocyte samples from 41 patients with malignant lymphoma have been shown to have depressed or undetectable levels of natural cytotoxicity against the leukaemic cell line K562 in a 4-hr [51Cr]-release assay. No correlation was found between low levels of natural killer (NK) cell activity and either the age of the patients, total or differential white blood counts, or the type or stage of disease. Furthermore, pre-treatment of lymphocytes with human lymphoblastoid (Namalva) interferon failed to enhance NK levels in 5/11 patients with Hodgkin's disease and 5/8 patients with non-Hodgkin's lymphoma, and was in contrast to the response of control peripheral blood lymphocytes assayed under the same test conditions. The lack of responsiveness to interferon of peripheral blood NK cells from lymphoma patients was not wholly associated with those patients shown to have low levels of spontaneous NK activity.


Stress-induced activation of the sympathetic nervous system.
Discrepancies between perceptions of internal or external circumstances and innate or acquired expectations lead to patterned stress responses involving several homeostatic systems, of which the sympathoadrenomedullary system (SAMS) is one. Severe, generalized threats such as hypoglycaemia, hypoxia, haemorrhage, circulatory collapse, and fight/flight situations elicit generalized SAMS activation, including cardiac stimulation, splanchnic, cutaneous, and renal vasoconstriction, and usually preserved skeletal muscle blood flow. Patterned sympathetic neural responses, resulting in redistribution of blood volume or changes in glandular activity, occur during orthostasis, exercise, altered environmental temperature, the postprandial state, and performance of attention-requiring tasks. In all these situations, SAMS activity is co-ordinated with that of the parasympathetic nervous system, the pituitary-adrenocortical system, and probably several neuropeptide systems. Although acute stress-induced SAMS activation can be a health hazard, the role of chronically repeated, stress-induced SAMS activation in the development of cardiovascular disease remains unclear. Benzodiazepines, beta-adrenoceptor blockers, and alpha 2-adrenoceptor agonists can attenuate effects of stress-induced SAMS activation, but pressor responses often are maintained.


Prognostic impact of morphology and duration of premature ventricular contractions in a population without structural heart disease.
Premature ventricular contractions (PVCs) are a common form of arrhythmia associated with an unfavorable prognosis in patients with structural heart disease. It is unclear whether PVCs site of origin and QRS-width has a prognostic significance in patients without structural heart disease. The aim of this study was to assess the prognostic importance of PVCs morphology and duration in this patient group. We included 511 consecutive patients without a history of previous heart disease. They were examined with echocardiography and exercise test with normal findings. We categorized the PVCs from a 12 lead ECG according to morphology and width of the QRS-complex and analyzed the outcome in terms of a composite endpoint of total mortality and cardiovascular morbidity. During a median follow-up time of 5.3 years, 19 patients (3.5%) died and 61 (11.3%) met the composite outcome. Patients with PVCs originating from the outflow tracts had a significantly lower risk for the composite outcome compared to patients with non-OT-PVCs. Similarly, patients with PVC originating from the right ventricle had a better outcome than patients with left ventricular PCVs. No difference in outcome depending on QRS-width during PVCs was noticed. In our cohort of consecutively included PVC patients without structural heart disease PVCs from the outflow tracts were associated with a better prognostic outcome than non-OT PVCs; the same was true for right ventricular PVCs when compared to left ventricular ones. The classification of the origin of the PVCs was based on 12-lead ECG morphology. QRS-width during PVC did not seem to have prognostic significance.


Diagnostic accuracy of the five times stand-to-sit test for the screening of global muscle weakness in community-dwelling older women.
Although the 5 times stand-to-sit test (5TSST) is indicated for screening for muscle weakness in older adults, its validity is based only on the correlation with quadriceps muscle strength or with the muscle strength of a few muscle groups of the lower limbs. Thus, the objective of the present study was to verify whether in independent older women, the 5TSST can really estimate global muscle strength, considering the sum of muscle strength of the trunk, hip, knee and ankle, which are important for functional activities. 119 independent older women participated in this cross-sectional study, undergoing the 5TSST and an isometric muscle strength assessment of the trunk, hip, knee and ankle, using an isokinetic dynamometer. The accuracy of the 5TSST for the discrimination of older women with reduced global muscle strength was evaluated by the ROC curve. The ROC curve showed that the 5TSST may discriminate older women with reduced global muscle strength with moderate accuracy (AUC = 0.783; 95 % CI = 0.681-0.886; p < 0.001). The 5TSST score with the best accuracy (sensitivity: 80.0 % and specificity: 61.8 %) to evaluate global muscle strength was 11.64 s. 5TSST can be used to identify reduced global muscle strength in independent older women, standing out as an accessible tool for the screening of muscle weakness.


Methotrexate removal during haemodialysis in a patient with advanced laryngeal carcinoma.
A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.


Biosimilarity Assessment of 2 Filgrastim Therapeutics in Healthy Volunteers.
This study aimed to compare the pharmacokinetic, pharmacodynamic, and safety profiles of a proposed biosimilar and innovator filgrastim therapeutics in healthy volunteers. In a crossover design, 23 subjects received a single subcutaneous injection of 300-µg filgrastim, followed by a 7-day washout period. Assessed pharmacokinetic parameters were the maximum observed filgrastim serum concentration (Cmax ), time to reach Cmax (tmax ), the area under the concentration-time curve (AUC), and elimination half-life. Pharmacodynamics were assessed by the maximum observed absolute neutrophil count effect (Emax ), tmax,E (time to reach Emax ), and the area under the effect of the absolute neutrophil count -time curve. The test/reference ratio (90% confidence intervals) of Cmax of 0.992 (0.860-1.143), AUC0-inf of 0.995 (0.891-1.111), Emax of 0.952 (0.841, 1.078), and area under the effect of the absolute neutrophil count -time curve from time zero to 96 hours of 0.939 (0.854-1.032), were all well within the predefined equivalence boundaries of 80% and 125%. Obtained values for tmax (∼4 hours), tmax,E (∼15 hours), and elimination half-life (∼3.5 hours) were comparable between 2 treatment groups. The local tolerability and incidence of adverse events were comparable, with no clinically meaningful difference between biosimilar and innovator products. Altogether, the results suggested a high similarity of the proposed biosimilar to the innovator filgrastim in healthy volunteers.


Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury.
Hydrogen sulfide (H2S) as a gaseous molecule prevents gastrointestinal (GI)-tract against various injuries. This study aimed to evaluate for the first time the detailed molecular mechanism of mitochondria-targeting H2S-prodrugs, AP39 and RT01 in gastroprotection against ischemia/reperfusion (I/R)-induced lesions. Wistar rats exposed to I/R were pretreated i.g. with vehicle, AP39 (0.004-2 mg/kg), RT01 (0.1 mg/kg), or with AP219 (0.1 mg/kg) as structural control without ability to release H2S. AP39 was also administered with mTOR1 inhibitor, rapamycin (1 mg/kg i.g.). Gastric damage area was assessed micro-/macroscopically, gastric blood flow (GBF) by laser flowmetry, mRNA level of HIF-1α, GPx, SOD1, SOD2, annexin-A1, SOCS3, IL-1RA, IL-1β, IL-1R1, IL-1R2, TNFR2, iNOS by real-time PCR. Gastric mucosal and/or serum content of IL-1β, IL-4, IL-5, IL-10, G-CSF, M-CSF, VEGFA, GRO, RANTES, MIP-1α, MCP1, TNF-α, TIMP1, FABP3, GST-α, STAT3/5 and phosphorylation of mTOR, NF-κB, ERK, Akt was evaluated by microbeads-fluorescent assay. Mitochondrial complexes activities were measured biochemically. RNA damage was assessed as 8-OHG by ELISA. AP39 and RT01 reduced micro-/macroscopic gastric I/R-injury increasing GBF. AP39-gastroprotection was accompanied by maintained activity of mitochondrial complexes, prevented RNA oxidation and enhanced mRNA/protein expression of SOCS3, IL-1RA, annexin-A1, GST-α, HIF-1α. Rapamycin reversed AP-39-gastroprotection. AP39-gastroprotection was followed by decreased NF-κB, ERK, IL-1β and enhanced Akt and mTOR proteins phosphorylation. AP39-prevented gastric mucosal damage caused by I/R-injury, partly by mitochondrial complex activity maintenance. AP39-mediated attenuation of gastric mucosal oxidation, hypoxia and inflammation involved mTOR1 and Akt pathways activity and modulation of HIF-1α, GST-α, SOCS3, IL1RA and TIMP1 molecular interplay.


Anatomic variations of feline internal and external jugular veins.
We evaluated 50 feline head and neck computed tomography examinations to determine the prevalence of vascular variation in the internal and external jugular veins. We identified three distinct anatomic conformations of the internal jugular vein. No variation of external jugular vein morphology was detected. Feline patients can have different internal jugular vein morphology that should be recognized for surgical planning.