Contrasting renal effects of nicotine in smokers and non-smokers.
Cigarette smoking is associated with acute increase in arterial pressure due to systemic vasoconstriction and decreased skin and coronary blood flow. Virtually all cardiovascular effects of cigarette smoking are due to nicotine. However, whether nicotine also affects the renal circulation and function in humans is at present unknown. In the current study the acute effects of a 4-mg nicotine gum on arterial pressure, heart rate as well as renal haemodynamics and function were assessed in non-smokers and chronic smokers. In non-smokers, mean arterial pressure (+8 +/- 1 mmHg, P<0.001) and heart rate (+13 +/- 3 beats/min, P<0.001) increased whereas effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) decreased by 15 +/- 4% and 14 +/- 4% respectively; in addition, urinary cyclic GMP decreased by 51 +/- 12% in response to nicotine administration. In smokers, mean arterial pressure and heart rate increased similarly; however, in contrast with non-smokers, ERPF and GFR remained unchanged whereas urinary cyclic GMP rose by 87 +/- 43%. Changes in ERPF induced by nicotine were positively correlated with changes in urinary cyclic GMP. These findings indicate that nicotine administration is associated with renal vasoconstriction in healthy non-smokers, possibly through alteration of a cyclic-GMP-dependent vasoactive mechanism. Tolerance to the renal effect of nicotine was observed in chronic smokers, despite the maintenance of the systemic response to nicotine.


Generation of oxygen radicals from iron complex of orellanine, a mushroom nephrotoxin; preliminary ESR and spin-trapping studies.
Orellanine, [2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide, is the toxin responsible for the lethal nephrotoxicity of some Cortinarius mushrooms. Our present ESR and spin-trapping studies of the redox properties of the system of non-illuminated orellanine, ferrous iron and dioxygen contribute to understanding the molecular mechanism of its toxicity. UV-visible spectrophotometry, cyclic voltammetry and ESR in frozen medium showed the formation of a wine-red tris complex, Fe(III)Or3. This ferric complex is easily reducible (Ep = -565 mV vs Ag/AgCl/3M KCl at pH 7), involving a one-electron reversible process. Spin-trapping using DMPO is employed to detect the generation of superoxide anion and hydroxyl radicals. The instantaneous one-electron oxidation of ferrous ions in the presence of the toxin under air is concomitant with dioxygen consumption as supported by dioxygen consumption. GSH involves the toxin and ferrous ions under air in a redox cycling process resulting in the production of glutathionyl and oxygen free radicals, observed for the first time with an iron complex of a mushroom toxin. In most cases, EDTA is not able to prevent the Fe(III)Or3 and radical formation. The ortho-dihydroxylated groups borne by the di-N-oxidized bipyridine structure and not the bipyridine structure itself, are responsible for the formation of a stable ferric complex at pH 7, as they are for the generation of an apparently stable ortho-semiquinone anion radical. These one-electron mechanisms may play a major role in some of the known toxic effects of orellanine.


Lead-Based Metal-Organic Framework with Stable Lithium Anodic Performance.
A microporous Pb-based metal-organic framework (MOF) [Pb(4,4'-ocppy)2]·7H2O (Pb-MOF) has been constructed from 4-(4-carboxyphenyl)pyridine N-oxide and Pb(NO3)2. Structural analysis reveals that the Pb-MOF possesses three-dimensional framework with a one-dimensional rhombic channel. When tested as a lithium-ion battery anode, a reversible lithium storage capacity of 489 mAh g-1 was maintained after 500 cycles at 100 mA g-1 as well as excellent cycling stability. The superior electrochemical performance may be derived from the sustenance of the Pb-MOF framework and compositional features of the organic moiety.


Early evidence of molariform hypsodonty in a Triassic stem-mammal.
Hypsodonty, the occurrence of high-crowned teeth, is widespread among mammals with diets rich in abrasive material, such as plants or soil, because it increases the durability of dentitions against wear. Hypsodont postcanine teeth evolved independently in multiple mammalian lineages and in the closely related mammaliaforms since the Jurassic period. Here, we report the oldest record, to our knowledge, of hypsodont postcanines in the non-mammaliaform stem-mammal, Menadon besairiei, from the early Late Triassic. The postcanines are long and columnar, with open roots. They were not replaced in older individuals and remained functional after the total wear of the crown enamel. Dental histology suggests that, convergently to hypsodont mammals, wear was compensated by the prolonged growth of each postcanine, resulting in dentine hypsodont teeth most similar to extant xenarthran mammals. These findings highlight the constraints imposed by limited tooth replacement and tooth wear in the evolutionary trajectories of herbivorous mammals and stem-mammals.


Invitro Antibacterial Activity of the Prosopis Juliflora Seed Pods on Some Common Pathogens.
Prosopis juliflora is probably the most widespread species of genus Prosopis and it is a good source of compounds that have been shown to be pharmacologically active. This plant has been used as a traditional treatment for several diseases. To investigate the in-vitro antibacterial activity of the P. juliflora seed pods from Bushehr, South West of Iran. In the present study, the antibacterial activity of P. juliflora seed pods extract was tested against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. The minimum inhibitory concentration (MIC) of the extract was determined for each test microorganism. P. juliflora seed pods extract exhibited antibacterial activity against all four test organisms. The MIC of the extract was 0.312 mg/ml and 0.078 mg/ml for S. aureus and S. epidermidis, respectively and 1.25 mg/ml for both E.coli and P.aeruginosa. P. juliflora seed pods from Bushehr, South West of Iran could be an appropriate source of antibacterial compounds that makes it a promising candidate for further studies.


Can larvae of the pod-borer, Helicoverpa armigera (Lepidoptera: Noctuidae), select between wild and cultivated pigeonpea Cajanus sp. (Fabaceae)?
Experiments were conducted to observe the feeding and food selection-behaviour of different instars of the pod-borer Helicoverpa armigera (Hübner) in response to choices between the cultivated and a wild species of Cajanus. First and second instars fed upon a cultivated variety of Cajanus cajan in preference to a wild species, C. scarabaeoides and on flowers of C. cajan, rather than pods or leaves of C. cajan. First and second instars preferred pods of C. scarabaeoides with trichomes removed to pods with trichomes present. All instars fed upon pods of C. cajan rather than those of C. scarabaeoides. Solvent extraction of the pod surfaces affected the feeding of larvae, in some instances. They preferred the unextracted pods of C. cajan; the extracted pod of C. scarabaeoides (first and second instars) or the unextracted pod of C. scarabaeoides (fourth and fifth instars). Glass-fibre disc bioassays showed that the methanol, hexane and water extracts from the pod-surface of C. cajan stimulated the feeding of fifth instars. The experiments have shown that characteristics of C. cajan, such as either the compounds present or the type and distribution of trichomes on the plant surfaces, can determine the susceptibility of C. cajan to pod-borer larvae.


An Organocatalytic Regiospecific Synthesis of 1,5-Disubstituted 4-Thio-1,2,3-triazoles and 1,5-Disubstituted 1,2,3-Triazoles.
Organocatalytic azide-ketone [3+2] cycloaddition (OrgAKC) of a variety of 1-aryl-2-(arylthio)ethanones and 1-alkyl-2-(alkylthio)ethanones with different aryl or alkyl azides is reported in dimethyl sulfoxide or solvent-free under ambient conditions to furnish 1,5-disubstituted 4-thio-1,2,3-triazoles in a regiospecific manner, which are further converted into useful 1,5-disubstituted 1,2,3-triazoles by treatment with Raney Ni at 25 °C for 1-3 h. Notable features of the OrgAKC reaction include high rate and selectivity, solvent-free conditions, easily available substrates and catalysts, a wide range of synthetic and medicinal applications, and excellent yields generating a vast library of triazoles.


Overexpression of CXCR7 is a Novel Indicator for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Patients.
To evaluate whether the overexpression of chemokine receptor-7 (CXCR7) in prostatic tissues obtained from men with Castration-Resistant Prostate Cancer (CRPC) is associated with resistance to enzalutamide (Enza). Based on the inclusion criteria of CRPC in EAU guidelines, all eligible patients treated in our hospital from January 2015 to December 2019 were included. Cases underwent radical prostatectomy, docetaxel-based chemotherapy, or new endocrine therapies (including Enza or abiraterone), and cases with severe cardiopulmonary disease or other malignant tumors were excluded. After immunohistochemical staining for CXCR7 expression in prostatic biopsy tissues, all enrolled cases were divided into two groups, namely, the CXCR7-positive group and the CXCR7-negative group. And then, PSA response to Enza treatment was recorded in detail and comparatively analyzed. In addition, the Cox proportional hazard modeling and the Kaplan-Meier analysis were used to determine PSA progression-free survival (PSAP-FS) and clinical or radiographic progression-free survival (CRP-FS) in this cohort. A total of 79 CRPC individuals were enrolled and evaluated in this study. Median follow-up durations were 24 months (range, 12-42) in the CXCR7-positive group (n = 47) and 28.5 months (range, 12-42) in the CXCR7-negative group (n = 32). The patients with lower CXCR7 expression showed much better PSA response to Enza treatment. There was 84.4% of CXCR7- cases showing decreasing PSA response, while there were 71.4% in the CXCR7/1+ group and 31.2% in the CXCR7/2+ group, respectively. All patients in the CXCR7/3+ group showed increasing PSA response to Enza treatment. And the percentage of patients whose PSA decreased over 50% is significantly higher in the CXCR7-negative group than in the CXCR7-positive group (68.8% vs. 8.5%, P < 0.001), and the percentage of patients whose PSA decreased over 90% is also remarkably higher in the CXCR7-negative group (43.8% vs. 0, P < 0.001). The Kaplan-Meier analysis demonstrated that the oncologic outcomes of CXCR7-negative patients were improved much significantly by Enza treatment in comparison with those of CXCR7-positive patients. Significantly increased median PSAP-FS (21 months vs. 6 months, P < 0.0001) and CRP-FS (27 months vs. 9 months, P < 0.0001) were obtained in the CXCR7-negative group. The further stratified analysis in all CXCR7-positive patients demonstrated that the patients with higher CXCR7 expression showed much worse outcome. The median time of PSAP-FS was 21 months in the CXCR7/1+ group, 9 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, while the median time of CRP-FS was 21 months in the CXCR7/1+ group, 12 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, respectively. Overexpression of CXCR7 induced by an AR antagonist in CRPC patients displays much better treatment response to Enza. CXCR7 might be a novel therapeutic target gene for CRPC patients.


Disparities in adolescent sleep health by sex and ethnoracial group.
Improving adolescent sleep health is a national priority for ameliorating health and wellbeing (Healthy People 2020), as the majority of adolescents do not get the minimum recommended amount of 8 h of sleep per night. Prior research has identified sex and ethnoracial disparities in adolescent sleep but has been limited by data availability. National studies have collected reported sleep data, while objective sleep data has been available in community samples only. Using new data from adolescents in the Fragile Families and Child Wellbeing Study, a population-based birth cohort study of children born 1998-2000, we are able to characterize sex and ethnoracial disparities in sleep health in the first national sample of actigraphy-assessed sleep health among adolescents. In cross-sectional analyses, we used linear and logistic regression models to assess sex and ethnoracial disparities in weekday sleep duration, timing, and quality measured using actigraphy collected from 738 adolescents at approximately age 15. We identified sex and ethnoracial group differences in weekday and weekend adolescent sleep duration, with larger disparities on weekends than weekdays. Male adolescents had 27-min shorter nightly sleep durations than females on weeknights. Non-Hispanic black adolescents had 32-min shorter nightly sleep durations than non-Hispanic whites on weekdays and 41-min shorter nightly sleep durations on weekends. While sex disparities persisted after accounting for naps, black-white differences were attenuated by napping such that there was no statistically significant black-white disparity in 24-h sleep on either weekdays or weekends. We did not identify disparities in sleep timing or quality. Future research should investigate the pathways through which these disparities arise, including behavioral and contextual mechanisms.


Problems and associated feelings experienced by family caregivers of stroke survivors the second and third month postdischarge.
This study identified problems and associated feelings experienced by family caregivers of stroke survivors during the second and third month after discharge from a rehabilitation facility to home. Safety was the most frequent problem identified by family caregivers. Other problems were managing activities of daily living (ADLs) and cognitive, behavioral, and emotional changes by stroke survivors. About half of caregivers expressed more positive feelings toward managing these problems by week 8 and the majority expressed these feelings by week 12.


No evidence of a lymphocytopenic state before manifestation of chronic lymphocytic leukemia.
Total lymphocyte counts were determined on an average 13.4 years before establishment of the diagnosis in 20 of 95 consecutive patients with chronic lymphocytic leukemia (CLL). The reasons for performing the white blood cell and differential counts did not include diabetes, autoimmune diseases or verified viral infections which are conditions well known to be associated with lymphocytopenia or lymphocytosis. The mean total lymphocyte count in the patient group was 2.6 X 10(9)/l and did not differ from that of an age-matched control group. There was no significant association between the pretreatment lymphocyte count and the time between test and diagnosis. We conclude that patients with CLL have not a lymphocytopenic state antedating the diagnosis of CLL.


Diagnosis and resection of a giant ovarian cyst presenting in a young patient with contralateral back pain and lower limb deep vein thrombosis.
We present a case of a giant ovarian cyst in a 20-year-old woman who presented atypically at our Emergency Department with left-sided back pain followed by acute left leg swelling. Blood tests showed significantly raised C-Reactive Protein and D-Dimer. CT-Abdomen-Pelvis demonstrated a large mass in the region of the right ovary with suspicious heterogeneous filling defects in the left external iliac vein, confirmed as a left-sided deep-vein thrombosis on ultrasound Doppler. MRI revealed the lesion to be cystic and the deep venous thrombosis was treated with twice-daily Clexane. Prior to removal of the cyst, an Inferior Vena Cava Filter was placed to reduce thromboembolic risk. The cyst was resected without complication and the postoperative period was uneventful. This case occurred while face-to-face services were limited by COVID-19 and illustrates the need for robust systemic measures to safeguard patients against the emergency sequelae of insidious gynaecological pathology.


Combinatorial DNA methylation codes at repetitive elements.
DNA methylation is an essential epigenetic modification, present in both unique DNA sequences and repetitive elements, but its exact function in repetitive elements remains obscure. Here, we describe the genome-wide comparative analysis of the 5mC, 5hmC, 5fC, and 5caC profiles of repetitive elements in mouse embryonic fibroblasts and mouse embryonic stem cells. We provide evidence for distinct and highly specific DNA methylation/oxidation patterns of the repetitive elements in both cell types, which mainly affect CA repeats and evolutionarily conserved mouse-specific transposable elements including IAP-LTRs, SINEs B1m/B2m, and L1Md-LINEs. DNA methylation controls the expression of these retroelements, which are clustered at specific locations in the mouse genome. We show that TDG is implicated in the regulation of their unique DNA methylation/oxidation signatures and their dynamics. Our data suggest the existence of a novel epigenetic code for the most recently acquired evolutionarily conserved repeats that could play a major role in cell differentiation.


Spherical polyelectrolyte brushes as a nanoreactor for synthesis of ultrafine magnetic nanoparticles.
Ultrafine magnetic nanoparticles (MNP, 1.4-5.8 nm) were generated within a nanoreactor of spherical polyelectrolyte brushes (SPB). SPB consist of a solid polystyrene (PS) core and densely grafted poly(acrylic acid) (PAA) chains. Due to strong chemical coordination between carboxyl groups in PAA and MNP surfaces, the obtained magnetic spherical polyelectrolyte brushes (MSPB) kept excellent stability and maintained pH sensitivity. The magnetic properties of MSPB were confirmed by a vibrating sample magnetometer (VSM). The size and the size dispersion of MNP can be modulated by varying adding sequences (conventional coprecipitation or reverse coprecipitation), or nanoreactor structure (with or without crosslinking). MNP content in MSPB could be adjusted by multicycle reactions. This new strategy makes it possible to synthesize ultrafine inorganic nanoparticles with tunable size in SPB.


Activity switching of Sn and In species in Heusler alloys for electrochemical CO2 reduction.
The electrochemical CO2 reduction reaction (CO2RR) activity of Ni2MnIn and Ni2MnSn Heusler alloys was investigated. Although pure In, Sn and Ni2MnIn generated formate as the major product, Ni2MnSn generated H2 as the major product. The CO2RR selectivity could be controlled by selecting the constituent elements of the intermetallic catalysts.


Upregulation of SOX9 promotes the self-renewal and tumorigenicity of cervical cancer through activating the Wnt/β-catenin signaling pathway.
Sry-box9 (SOX9) maintains stem cell properties and plays crucial roles in many cancers. However, whether SOX9 is correlated with cervical cancer cell stemness and its detailed mechanism remains obscure. We studied the relationship between SOX9 and prognosis of cervical cancer through public database, and SOX9 was related to poor prognosis of cervical cancer. Elevated SOX9 expression enhanced the self-renewal properties and promotes tumorigenicity in cervical cancer. Overexpression of SOX9 could promote the expression of stem cell-related factors in cervical cancer cells and xenografts. Meanwhile, overexpression of SOX9 could also enhance the expressions of FZD10, β-catenin, and c-Myc in cervical cancer cells and xenografts, while inhibiting the expression of DDK1. The activation of Wnt pathway by chir-99 021 raised the tumor spheroid ability of SOX9 knockdown HeLa cells. In addition, SOX9 could transcriptional inhibit DKK1 and activate FZD10 and MYC by binding to their promoters to affect the Wnt/β-catenin pathway. These results demonstrated SOX9 regulated the self-renewal and tumorigenicity of cervical cancer through Wnt/β-catenin pathway by directly transcriptional activation of FZD10, MYC and transcriptional inhibition of DKK1.


Review of East Palaearctic species of Sympycnus Loew, 1857, with a key to species.
Four new species of Sympycnus Loew, 1857, S. ferganicus sp. nov., S. leleji sp. nov., S. stackelbergi sp. nov. and S. yakutensis sp. nov. from Russia (Yakutia), Kazakhstan, Kyrgyzstan, Tajikistan and Uzbekistan are described. Sympycnus convergens Negrobov, 1973 and S. urgaicus Negrobov, 1973 are placed in synonymy with S. changaicus Negrobov (syn. nov.). Lectotype and paralectotypes are designated for Sympycnus simplicipes Becker, 1908. A checklist of the East Palaearctic species of the genus is compiled and a key to males of the 14 species is provided. Five species groups are defined. New data on the distribution of known species are presented. The known distribution of East Palaearctic Sympycnus species is briefly discussed.


Sleep-disordered breathing is an independent risk factor of aborted sudden cardiac arrest in patients with coronary artery spasm.
Sleep-disordered breathing (SDB) is often associated with sudden cardiac arrest (SCA) during sleep. Coronary artery spasm (CS) also occurs during sleep and is rarely associated with SCA, but the role of SDB in the risk of SCA is unknown in CS patients. This study evaluated the breathing patterns during sleep in CS patients with a prior history of aborted SCA. This study enrolled 24 patients (age 61.6 ± 11.0 years, male/female 19/5) with CS proven by an acetylcholine provocation test. They were divided into 2 groups: prior history of aborted SCA due to fatal arrhythmia (SCA group; n=9) and no such history (no-SCA group; n=15). Patients underwent overnight polysomnography with ambulatory electrocardiography. The overall prevalence of SDB (apnea hypopnea index ≥15) was 45.8% in this cohort. SDB was more frequent in the SCA group than in the no-SCA group (88.9% vs. 20.0% P=0.001) and identified as a pivotal risk factor of aborted SCA (odds ratio: 38.9, 95% CI: 2.80-1,498.2, P=0.01). Very-low-frequency was significantly correlated with the apnea hypopnea index in patients with SCA (P=0.01, r=0.78) during sleep. SDB is a significant risk factor for SCA in CS patients and autonomic instability during sleep might be involved in this association.


NFAT interactions with the vasoactive intestinal peptide cytokine response element.
The vasoactive intestinal peptide cytokine response element (VIP CyRE) is responsible for mediating the transcriptional induction of the VIP gene to the neuropoietic cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). In investigating the sequence and function of the CyRE, we found a region of DNA with homology to the distal NFAT site in the IL-2 promoter. In this paper we characterize this sequence and show that the VIP NFAT site recognizes T cell NFAT with similar affinity to the previously characterized IL-2 NFAT site. However, despite its location in the middle of the CyRE, we find no CNTF/LIF induced binding to it. Instead we show that in NBFL neuroblastoma cells, the calcium ionophore A23187 induces a protein to bind to the VIP NFAT site. This A23187-mediated induction of nuclear protein binding to an NFAT oligonucleotide is dependent on extracellular calcium but not dependent on de novo protein synthesis. Thus, this protein has the characteristics of an NFAT-like protein and is recognized by an NFAT3-specific antiserum suggesting that it is indeed an NFAT protein. The location of the NFAT site in the VIP CyRE suggests that this may be one mechanism through which different signaling pathways engage in cross talk to alter VIP gene transcription.


Pre-registration children's and young people's nurse preparation. A SWOT analysis.
An investigation was undertaken into the views of nurse educators on current approaches to preparing children's and young people's nurses in the UK. A convenience sample of lead academics in 17 child health nursing departments of British universities was contacted by email and invited to liaise with colleagues to generate lists of the strengths, weaknesses, opportunities and threats (SWOT) of the educational system. Thirteen departments provided data that were analysed and themed. Major themes included the common foundation programme, clinical skills learning, clinical placements and employment. More detailed evaluative work should be undertaken before wholesale changes are made to a relatively new curriculum.


Towards a simplified description of thermoelectric materials: accuracy of approximate density functional theory for phonon dispersions.
We calculate the phonon-dispersion relations of several two-dimensional materials and diamond using the density-functional based tight-binding approach (DFTB). Our goal is to verify if this numerically efficient method provides sufficiently accurate phonon frequencies and group velocities to compute reliable thermoelectric properties. To this end, the results are compared to available DFT results and experimental data. To quantify the accuracy for a given band, a descriptor is introduced that summarizes contributions to the lattice conductivity that are available already in the harmonic approximation. We find that the DFTB predictions depend strongly on the employed repulsive pair-potentials, which are an important prerequisite of this method. For carbon-based materials, accurate pair-potentials are identified and lead to errors of the descriptor that are of the same order as differences between different local and semi-local DFT approaches.


Reovirus strain-dependent inflammatory cytokine responses and replication patterns in a human monocyte cell line.
Mammalian Orthoreoviruses are important models for studies of viral pathogenesis. In the rat lung, Reovirus strain type 3 Dearing (T3D) induces substantially more inflammation than does strain type 1 Lang (T1L). To better understand mechanisms underlying differences in the host inflammatory response elicited by T1L and T3D, we characterized cytokine expression patterns induced by those strains after infection of THP-1 monocyte cells. THP-1 cells were adsorbed with either viable or ultraviolet- inactivated T1L and T3D and assayed for mRNA and protein production of growth-regulated oncogene-alpha (GRO-alpha), interleukin-8 (IL-8), or tumor necrosis factor-alpha (TNF-alpha). T3D stimulated mRNA and protein production of all three cytokines, whereas T1L stimulated mRNA and protein production of IL-8 and TNF-alpha but not GRO-alpha. In each case, T3D induced greater cytokine mRNA and protein expression than did T1L. Nonviable virus did not stimulate detectable cytokine secretion, suggesting a requirement for viral RNA synthesis in cytokine induction by THP-1 cells. A greater percentage of THP-1 cells was infected with T1L than T3D as assessed by infectious center assay, and T1L achieved higher yields of infectious progeny than did T3D in infected THP-1 cells as determined by plaque assay. These strain-dependent differences in cytokine responses and corresponding replication patterns in monocyte cells parallel findings made in studies of rat models of pneumonia and provide clues about how Reovirus interfaces with the host innate immune response to produce pulmonary disease.


The colorful history of active DNA demethylation.
Patterns of DNA cytosine methylation are subject to mitotic inheritance in both plants and vertebrates. Plants use 5-methylcytosine glycosylases and the base excision repair pathway to remove excess cytosine methylation. In mammals, active demethylation has been proposed to operate via several very different mechanisms. Two recent reports in Nature now claim that the demethylation process is initiated by the same enzymes that establish the methylation mark, the DNA methyltransferases DNMT3A and DNMT3B (Kangaspeska et al., 2008; Métivier et al., 2008).


Serum PAF-acetylhydrolase in severe renal or hepatic disease in man: relationship to circulating levels of PAF and effects of nephrectomy or transplantation.
(1) PAF-acetylhydrolases form a major pathway for the degradation of platelet-activating factor (PAF). Here we investigate the role of the kidney and the liver in the control of PAF-acetylhydrolase levels by comparing normal subjects to patients with abnormal liver or kidney function. These patients had either severe chronic liver disease, chronic renal failure or were anephric. In a few cases PAF was also measured. (2) In those patients where PAF was measured there was no evidence that circulating PAF levels determined PAF-acetylhydrolase release. (3) In anephric patients serum PAF-acetylhydrolase levels were normal or even raised. Therefore the kidney is unlikely to be the usual major source of serum PAF-acetylhydrolase in man. (4) Liver patients with chronic cholestasis had elevated serum PAF-acetylhydrolase especially in stage III or IV primary biliary cirrhosis, as well as in a patient with secondary biliary cirrhosis and one with cholangiocarcinoma. Since normalisation of liver function following liver transplantation was accompanied by a reduction to normal or near normal PAF-acetylhydrolase levels, it is likely that the liver can play an important role in regulating levels of this enzyme in serum.


Simultaneous determination of estramustine phosphate and its four metabolites in human plasma by liquid chromatography-ionspray mass spectrometry.
A sensitive and selective method, using liquid chromatography-ionspray mass spectrometry, was developed and validated for the simultaneous determination of Estracyt (estramustine phosphate) and its four metabolites, estramustine, estromustine, estrone and estradiol, in human plasma. Deuterated internal standards were available for all analytes. The five compounds were extracted from plasma by protein precipitation with acetonitrile. The chromatographic separation was performed using a Zorbax SB C18, (150 x 4.6 mm i.d., 5 microm) reversed-phase column under gradient conditions with a mobile phase containing 2 mm ammonium acetate buffer (pH 6.8) and acetonitrile. MS detection was by electrospray ionization with multiple reaction monitoring in the positive ion mode for estramustine phosphate, estromustine and estramustine, and in the negative ion mode for estrone and estradiol. The limit of quantitation was 10 ng/mL for estramustine phosphate, 3 ng/mL for estromustine, estramustine and estrone and 30 ng/mL for estradiol. Linearity was verified from these LLOQs up to about 4000 ng/mL for the parent drug and 2000 ng/mL for the metabolites. Inter-day precision and accuracy values were all less than 15%. This assay was applied successfully to the routine analysis of human plasma samples collected in cancer patients administered estramustine phosphate intravenously.


Evaluation of an immunomagnetic separation-real-time PCR assay for the rapid detection of Salmonella in meat.
The aim of this study was the comparison of an immunomagnetic separation (IMS)-real-time PCR assay for the detection of Salmonella with the cultural reference method according to and 35 of the German Law on Food and Commodities (LMBG, L 00.00.20:1998). The IMS-real-time PCR assay includes a nonselective preenrichment step, an IMS, DNA extraction, as well as DNA purification followed by hybridization probe-based real-time PCR analysis. An accurate comparability was achieved, because both methods analyzed the same preenrichment. The evaluation was carried out using both artificially and naturally contaminated meat samples. The IMS-real-time PCR assay provides a result after 12 to 13 h. Compared with the reference method and regarding artificially contaminated meat samples, the IMS-real-time PCR assay achieved a specificity of 80% (false-positive rate of 20%) and a sensitivity of 100% (false-negative rate of 0%). The relative accuracy was 94%. The detection limit of both methods was 10 CFU/25 g. The concordance index kappa, which defines the statistical accordance, was 0.85 and indicated the agreement of both methods on statistical criteria. Compared to the reference method and analyzing naturally contaminated meat samples (n = 491), the IMS-real-time PCR assay showed a specificity of 99.3% (false-positive rate of 0.7%) and a sensitivity of 83.7% (false-negative rate of 16.3%). The relative accuracy was 98%. The concordance index kappa had a value of 0.87 and highlighted the statistical agreement of both methods. In conclusion, the IMS-real-time PCR assay is suitable as specific, sensitive, and rapid screening method for the detection of Salmonella from meat.


Primary structure and expression of a chicken laminin beta chain: evidence for four beta chains in birds.
Characterization of a full length cDNA sequence for a chicken laminin beta chain is described which is most closely related to the mammalian beta 2 chain. Comparison with published sequences shows that the chicken beta 2-like chain corresponds to a fragment of a previously described laminin beta chain called B1-2 (O'Rear, 1992). The sequence of the chicken beta 2-like chain differed from fragments of two other chicken laminin beta chains that were previously described and designated B1-1 (now called beta 1; O'Rear, 1992) and beta x (Ybot-Gonzalez et a1.,1995). In addition, the beta 2- like chain does not appear to be the chicken equivalent of the mammalian laminin beta 3 chain, since it differs markedly in cDNA sequence, possesses domain IV and has a transcript size of 6 kb. We therefore propose that there are at least four laminin beta chains in the chicken. Sequence comparison of the beta 2-like laminin chain with previously cloned beta 1 and beta 2 chains shows a somewhat closer relationship to rat and human beta 2 than to mouse and human beta 1, especially in domains I, II and alpha. In addition, two expressed fragments of the chicken beta 2-like chain were recognized by a monoclonal antibody (C4) regarded as specific for the rat beta 2 chain (Hunter et al., 1989a). The results therefore suggest that the laminin chain previously described as a potentially novel chain called B1-2 (O'Rear, 1992) is likely to be the chicken equivalent of the mammalian beta 2 chain.


Evidence-Based Brief Psychological Treatment for Emotional Disorders in Primary and Specialized Care: Study Protocol of a Randomized Controlled Trial.
Emotional Disorders (EDs) are very prevalent in Primary Care (PC). However, general practitioners (GPs) have difficulties to make the diagnosis and the treatment of this disorders that are usually treated with drugs. Brief psychological therapies may be a new option to treat EDs in a PC context. This article aims to present a study protocol to evaluate the effectiveness and the efficiency of an adaptation to brief format of the "Unified Protocol (UP) for the transdiagnostic treatment of EDs." This is a single-blinded RCT among 165 patients with EDs. Patients will be randomly assigned to receive brief psychological treatment based on UP, conventional psychological treatment, conventional psychological treatment plus pharmacological treatment, minimum intervention based on basic psychoeducational information, or pharmacological treatment only. Outcome measure will be the following: GAD-7, STAI, PHQ-9, BDI-II, PHQ-15, PHQ-PD, and BSI-18. Assessments will be carried out by blinded raters at baseline, after the treatment and 6-month follow-up. The findings of this RCT may encourage the implementation of brief therapies in the PC context, what would lead to the decongestion of the public health system, the treatment of a greater number of people with EDs in a shorter time, the reduction of the side effects of pharmacological treatment and a possible economic savings for public purse. Clinical Trial Registration: ClinicalTrial.gov, identifier NCT03286881. Registered September 19, 2017.


Discriminating between different pathways of memory CD8+ T cell differentiation.
Despite the rapid accumulation of quantitative data on the dynamics of CD8(+) T cell responses following acute viral or bacterial infections of mice, the pathways of differentiation of naive CD8(+) T cells into memory during an immune response remain controversial. Currently, three models have been proposed. In the "stem cell-associated differentiation" model, following activation, naive T cells differentiate into stem cell-like memory cells, which then convert into terminally differentiated short-lived effector cells. In the "linear differentiation" model, following activation, naive T cells first differentiate into effectors, and after Ag clearance, effectors convert into memory cells. Finally, in the "progressive differentiation" model, naive T cells differentiate into memory or effector cells depending on the amount of specific stimulation received, with weaker stimulation resulting in formation of memory cells. This study investigates whether the mathematical models formulated from these hypotheses are consistent with the data on the dynamics of the CD8(+) T cell response to lymphocytic choriomeningitis virus during acute infection of mice. Findings indicate that two models, the stem cell-associated differentiation model and the progressive differentiation model, in which differentiation of cells is strongly linked to the number of cell divisions, fail to describe the data at biologically reasonable parameter values. This work suggests additional experimental tests that may allow for further discrimination between different models of CD8(+) T cell differentiation in acute infections.


Feasibility of telesurgery in the modern era.
Telesurgery is not a foreign concept and dates to as early as the 1920s. The use of robots in medicine has had a very positive effect and improved outcomes with little to no adverse effects. Having global access to telemedicine and telesurgery during the COVID-19 pandemic and being able to provide top medical care to gravely ill and contagious patients without compromising the safety of the medical team would be a very big achievement. We explore the hurdles needed to make it a realistic goal and give recommendations to achieve it utilizing the major advancements that have occurred over the past few years in the fields of engineering, communication etc. The biggest issues needed to be addressed are of financial investment, legal concerns, and availability of high-speed uninterrupted data connections.


Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides--reaction discovery using parallel microscale experimentation.
Microscale parallel experimentation was used to discover three catalyst systems capable of coupling secondary organotrifluoroborates with sterically and electronically demanding aryl chlorides and bromides. The ensuing results represent the first comprehensive study of alkylboron coupling to aryl chlorides and, in particular, using secondary alkylboron partners. A ligand-dependent beta-hydride elimination/reinsertion mechanism was implicated in the cross-coupling of more hindered substrates, leading to isomeric mixtures of coupled products in some cases.


Antitumor activity and antioxidant status of Streblus asper bark against Dalton's ascitic lymphoma in mice.
Streblus asper Lour (Moraceae), commonly known as Siamee Rough Brush in English is widely distributed in subtropical Asia and traditionally used for several medicinal purposes. In the present study, the ethyl acetate fraction of the methanol extract from Streblus asper bark (EASA) was evaluated for antitumor effect against Dalton's ascitic lymphoma (DAL) in Swiss albino mice. Twenty-four hours after intraperitoneal inoculation of DAL cells in mice, EASA was administered intraperitoneally at 200 and 400 mg/kg body weight for 9 consecutive days. On the 10th day, half of the mice were sacrificed to determine the tumor growth parameters, and the rest were kept alive for survival assessment. Hematological, serum biochemical and tissue (liver, kidney) antioxidant profiles were also determined. EASA exhibited significant and dose dependent decrease in tumor growth parameters and increased survival of DAL bearing animals. EASA significantly and dose-dependently normalized the altered hematological, serum biochemical and tissue antioxidant parameters as compared with the DAL control mice. From the present study it may be concluded that S. asper bark possesses remarkable antitumor efficacy mediated by amelioration of oxidative stress by multiple mechanisms.


Contrast-enhanced transvaginal sonography of benign versus malignant ovarian masses: preliminary findings.
The aim of this prospective study was to evaluate differences in contrast enhancement and contrast enhancement kinetics in benign versus malignant ovarian masses with pulse inversion harmonic transvaginal sonography. Seventeen consecutive patients with 23 morphologically abnormal ovarian masses (solid or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10 cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic transvaginal sonography. The following parameters were assessed in all tumors: detectable contrast enhancement, time to peak enhancement (wash-in), peak contrast enhancement, half wash-out time, and area under the enhancement curve. Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors. Fourteen benign masses and 9 malignancies were studied. There was a statistically significant difference in the peak enhancement (mean +/- SD, 23.3 +/- 2.8 versus 12.3 +/- 3.9 dB; P < .01), half wash-out time (139.9 +/- 43.6 versus 46.3 +/- 19.7 seconds; P < .01), and area under the enhancement curve (2012.9 +/- 532.9 versus 523.9 +/- 318 seconds(-1); P < .01) in malignant masses compared with benign disease. There was no statistically significant difference in the time to peak enhancement (26.1 +/- 6.3 versus 24.9 +/- 7.6 seconds; P = .07). Overall, our data showed a significant difference in the contrast enhancement kinetic parameters between benign and malignant ovarian masses.


Paternal exposure and counselling: experience of a Teratology Information Service.
We describe paternal exposure and counselling in a selected population calling to an Italian Teratology Information Service (TIS). The majority of callers asked for paternal drug exposure (76%, drugs except chemotherapy) and treatment for cancer (17%, chemotherapy and/or radiotherapy). Others asked for exposure to diagnostic radiations (4%), recreational drugs (2%) and occupational chemicals (1%). Among paternal drugs neurological compounds, immunosuppressive drugs and antiviral agents were the main reasons for calling. In humans, there are no evidences of birth defects after paternal exposures, but to minimize any possible risk, counselling in men exposed to radio and chemotherapy should recommend delaying conception for at least 3 months after the end of the therapy. Male patients treated with drugs, whose teratogenic potential has been well assessed or suspected for maternal exposure, should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy.


Intracellular reservoir of Streptococcus pyogenes in vivo: a possible explanation for recurrent pharyngotonsillitis.
Numerous theories have been presented that attempt to explain the frequent recurrences of pharyngotonsillitis caused by Streptococcus pyogenes; these recurrences occur after seemingly adequate antibiotic treatment. We previously have demonstrated that Spyogenes can survive for up to 7 days intracellularly in immortalized human respiratory epithelial cells grown in an antibiotic supplemented medium. Viable S pyogenes were externalized and established an extracellular infection, whenever the extracellular antibiotic was removed. We have investigated the presence of intracellular S pyogenes in two in vivo studies using respiratory epithelial cells collected from patients with tonsillitis and the tonsils of asymptomatic carriers. Electron microscopy and immunohistochemistry demonstrated intracellular S pyogenes in pharyngeal epithelial cells in 13 of 14 patients with tonsillitis (93%). Furthermore, intracellular S pyogenes were found in macrophage-like cells in eight (73%) and in epithelial cells in four (36%) tonsils from 11 asymptomatic S pyogenes carriers. These in vivo data strongly support the hypothesis that intracellular S pyogenes can constitute a reservoir of bacteria with the potential to cause reinfections.


Improved diagnosis of unilateral renal artery lesions after captopril administration.
Captopril was administered (1 mg/kg of body weight) to 37 unselected hypertensive patients undergoing bilateral renal vein catheterization to determine its safety and efficacy in diagnosing hypertension related to unilateral renal artery lesions. In the 18 patients who had a unilateral renal artery lesion demonstrated by angiography, the ratio of plasma renin activity of the involved to uninvolved renal vein rose significantly after administration of captopril, whether or not patients were taking antihypertensive medication. This postcaptopril ratio differentiated cases of unilateral lesions from cases of bilateral lesions or absence of lesions without any overlap. The test was well tolerated despite occasional large drops in blood pressure. These data show that converting enzyme inhibition increases the diagnostic accuracy of renal vein catheterization by increasing the difference between the amount of plasma renin secreted by the two kidneys in cases of unilateral renal artery lesions.


Improving Rice Leaf Shape Using CRISPR/Cas9-Mediated Genome Editing of SRL1 and Characterizing Its Regulatory Network Involved in Leaf Rolling through Transcriptome Analysis.
Leaf rolling is a crucial agronomic trait to consider in rice (Oryza sativa L.) breeding as it keeps the leaves upright, reducing interleaf shading and improving photosynthetic efficiency. The SEMI-ROLLED LEAF 1 (SRL1) gene plays a key role in regulating leaf rolling, as it encodes a glycosylphosphatidylinositol-anchored protein located on the plasma membrane. In this study, we used CRISPR/Cas9 to target the second and third exons of the SRL1 gene in the indica rice line GXU103, which resulted in the generation of 14 T0 transgenic plants with a double-target mutation rate of 21.4%. After screening 120 T1 generation plants, we identified 26 T-DNA-free homozygous double-target mutation plants. We designated the resulting SRL1 homozygous double-target knockout as srl1-103. This line exhibited defects in leaf development, leaf rolling in the mature upright leaves, and a compact nature of the fully grown plants. Compared with the wild type (WT), the T2 generation of srl1-103 varied in two key aspects: the width of flag leaf (12.6% reduction compared with WT) and the leaf rolling index (48.77% increase compared with WT). In order to gain a deeper understanding of the involvement of SRL1 in the regulatory network associated with rice leaf development, we performed a transcriptome analysis for the T2 generation of srl1-103. A comparison of srl1-103 with WT revealed 459 differentially expressed genes (DEGs), including 388 upregulated genes and 71 downregulated genes. In terms of the function of the DEGs, there seemed to be a significant enrichment of genes associated with cell wall synthesis (LOC_Os08g01670, LOC_Os05g46510, LOC_Os04g51450, LOC_Os10g28080, LOC_Os04g39814, LOC_Os01g71474, LOC_Os01g71350, and LOC_Os11g47600) and vacuole-related genes (LOC_Os09g23300), which may partially explain the increased leaf rolling in srl1-103. Furthermore, the significant downregulation of BAHD acyltransferase-like protein gene (LOC_Os08g44840) could be the main reason for the decreased leaf angle and the compact nature of the mutant plants. In summary, this study successfully elucidated the gene regulatory network in which SRL1 participates, providing theoretical support for targeting this gene in rice breeding programs to promote variety improvement.


Pulmonary function after complete unilateral phrenic nerve transection.
The status of pulmonary function following phrenic nerve transfer surgery is still largely unknown because of the high degree of variability in the accessory phrenic nerve that may be involved. In the present study, pulmonary functions were assessed in patients before and after full-length phrenic nerve transfer surgery, in whom the phrenic nerve was severed at a location just before its entry into the diaphragm. Fifteen patients (average age 27.4 years) with complete brachial plexus palsy underwent full-length phrenic nerve transfer. The phrenic nerve was harvested from the thoracic cavity by means of video-assisted thoracic surgery and then transferred to the musculocutaneous nerve. Postoperative pulmonary functions were retrospectively analyzed. Patients underwent follow-up evaluation for 42 to 48 months; four patients were eventually lost to follow up. Although no patient experienced pulmonary problems following the surgery, all sustained varying degrees of diaphragmatic paralysis and elevation (for 1-1.5 intercostal spaces) on the surgically treated side as seen on chest x-ray films. Pulmonary functional parameters, including vital capacity, vital capacity in percentage of predicted values, residual volume, total lung capacity, forced vital capacity, and forced expiratory volume in 1 second, recovered to preoperative levels by 1 year postsurgery. In contrast, the postoperative maximal inspiratory pressure value was significantly decreased compared with the predicted values (average decrease approximately 20%) in all of the patients, even at 4 years after the surgery. In young patients with healthy lung function, unilateral phrenic nerve transection surgery can cause unilateral diaphragmatic paralysis and reduce the inspiration muscle force; however, most pulmonary function parameters gradually recover to preoperative levels within 1 year.


[Direct detection of an antigen in immunoglobulin G Langmuir-Blodgett films based on a surface plasma resonance method and in a piezoelectric system].
The possibilities of direct antigen detection in unlabelled systems based on immunoglobulin G Langmuir-Blodgett films as a sensitive surface have been studied. It was shown that an increase in the monolayer number in an immunoglobulin G Langmuir-Blodgett film deposited onto a solid surface coated with a thin silver film (50 nm) resulted in the regeneration of the antigen-binding capacity of the upper antibody layer. This dependence can be used for the construction of a direct optical immunosensor based on surface plasmon resonance. Moreover, a model of a piesoelectric immunosensor on the basis of immunoglobulin G Langmuir-Blodgett films for direct ferritin detection has been proposed. The detection range of ferritin concentrations in solution is 10(-10)-10(-7) M.


Challenges for biomarkers in cancer detection.
Cancer remains the leading cause of death in the United States. Biomarkers can be used to detect cancer in different stages, initiation, development, and progression. The desirable property and utility of a biomarker lie in its ability to provide an early indication of disease progression. Biomarkers should be easy to detect, measurable across populations, and useful for detection of cancer at an early stage, identification of high-risk individuals, detection of recurrence, or monitoring endpoints in intervention studies. Recent technological advances have helped develop noninvasive, sensitive, and specific biomarkers to detect cancer at early stages of the disease.


Alcohol and other drug abuse in elders.
With the growing population of older persons, ET nurses can expect an increasing number of elderly clients in their practice settings. Elderly persons are not immune to alcohol and other drug abuse. Detection of substance abuse in this population is complex and often missed. The purposes of this article are as follows: (1) examine barriers that may prevent nurses from addressing substance abuse among the elderly population; (2) suggest risks for psychoactive substance abuse in this population; (3) identify warning signs that should alert nurses to the problem; and (4) outline treatment options for substance-abusing clients.


[Propafenon therapy of arrhythmias in infancy and childhood (author's transl)].
The therapeutic dose range of propafenon was studied in 28 infants and children aged 5 days to 15.2 years (mean 8.8 years) with the following cardiac arrhythmias: paroxysmal tachycardia (20) atrial flutter (5) ventricular extrasystoles (2) and junctional tachycardia (1). With the intravenous administration of the drug in a dosage of 1.03-3.2 mg/kg/d (mean 2.28 mg/kg/d) in patients less than 15 kg and of 0.71-2.06 mg/kg/d (mean 1.26 mg/kg/d) in patients more than 15 kg body weight arrhythmias abolished. In the same patients the oral dosage was 12.2-22.6 mg/kg/d (mean 16.03 mg/kg/d) and 7.2-16.6 (mean 11.12 mg/kg/d). After 10 to 14 days a therapeutic serum level above 150 ng/ml could be maintained by a reduced oral dosage of 5.7-13.3 mg/kg/d) mean 8.5 mg/kg/d) and 3.6-11.1 mg/kg/d (mean 6.33 mg/kg/d) respectively. There were no side effects except for transitory by elevated gamma-GT in 8 patients. During a follow-up period of 1 month to 2.2 years (mean 1.6 years) 20 patients had no more arrhythmias, in 7 the number of arrhythmic attacks was reduced, and in 1 therapy failed.


Further observations on asymmetrical solute movement across membranes.
The permeability of frog skin under the influence of urea hyperosmolarity has been studied. Flux ratio asymmetry has been demonstrated again for tracer mannitol. The inhibitors DNP, CN(-), and ouabain have been used to eliminate active sodium transport and it was found that urea hyperosmolarity produces asymmetrical mannitol fluxes on frog skins having no short-circuit current. These findings suggest that flux ratio asymmetry is due to solute interaction and is unrelated to sodium transport. Studies with a synthetic membrane show clearly that bulk flow of fluid can produce a "solvent drag" effect and change flux ratios. When bulk flow is blocked and solute gradients allowed their full expression, then solute interaction "solute drag" is easily demonstrable in a synthetic system.


Uniport of monoanionic L-malate in membrane vesicles from Leuconostoc oenos.
L-malate transport was studied in membrane vesicles from Leuconostoc oenos MLE(-) (mutant lacking malolactic enzyme) which were fused with liposomes containing beef heart cytochrome c oxidase as a proton-motive-force-generating system. In these hybrid membranes, accumulation of L-malate was observed in response to a pH gradient (delta pH), with the inside alkaline, but was strongly inhibited by a membrane potential (delta psi) of normal polarity (inside negative). Imposition of a delta psi, with the inside positive, by means of valinomycin-mediated potassium influx, resulted in a rapid accumulation of L-malate, indicating that L-malate was taken up in an anionic form. The results are consistent with a uniport mechanism facilitating the uptake of monoanionic L-malate, the dominant species at the low pH of the experiments. Kinetic analysis of delta pH-driven L-malate uptake in the pH range 3.0-5.8, yielded apparent affinity constants that varied less than twofold when calculated on the basis of the concentrations of monoanionic L-malate, whereas the values differed 2-3 orders of magnitude for the other species. At L-malate concentrations above 1 mM, a non-saturable transport component became apparent which may reflect passive influx of L-malic acid. Substrate specificity studies indicated that citrate and L-malate (and possibly D-lactate and L-lactate) compete for a single general carboxylate transport system. The carboxylate transport system catalysed homologous L-malate and heterologous L-malate/citrate exchange with rates similar to the rate of L-malate efflux. Since metabolic energy is conserved during malolactic fermentation in L. oenos, the underlying mechanism most likely involves electrogenic monoanionic L-malate uptake, in combination with H+ consumption in the cytoplasm, followed by diffusion outwards of lactic acid plus carbon dioxide.


Characterization of two Streptomyces ambofaciens recA mutants: identification of the RecA protein by immunoblotting.
The recA gene was isolated from Streptomyces ambofaciens DSM40697. Its nucleotide sequence predicted a protein of 372 residues. Two recA mutants, NSAR1001 and NSAR57, obtained by gene disruption encoded a RecA protein lacking respectively 30 and at least 62 amino acids from the C-terminal end. NSAR1001 showed a wild-type sensitivity to UV light and oxolinic acid. In contrast, NSAR57 was highly sensitive to these agents and the loss of the inserted DNA restored the wild-type phenotype. Western blot analysis using antiserum to Escherichia coli RecA showed that overproduction of RecA was correlated with overtranscription of recA in an S. ambofaciens amplified mutant derived from genetic instability.


Rapid Voltammetric Measurements at Conducting Polymer Microelectrodes Using Ultralow-Capacitance Poly(3,4-ethylenedioxythiophene):Tosylate.
We use a vapor-phase synthesis to generate conducting polymer films with low apparent capacitance and high conductance enabling rapid electrochemical measurements. Specifically, oxidative chemical vapor deposition was used to create thin films of poly(3,4-ethylenedioxythiophene):tosylate ( tosylate). These films had a conductance of 17.1 ± 1.7 S/cm. Furthermore, they had an apparent capacitance of 197 ± 14 μF/cm(2), which is an order of magnitude lower than current commercially available and previously reported PEDOT. Using a multistage photolithography process, these films were patterned into tosylate microelectrodes and were used to perform fast-scan cyclic voltammetry (FSCV) measurements. Using a scan rate of 100 V/s, we measured ferrocene carboxylic acid and dopamine by FSCV. In contrast to carbon-fiber microelectrodes, the reduction peak showed higher sensitivity when compared to the oxidation peak. The adsorption characteristics of dopamine at the polymer electrode were fit to a Langmuir isotherm. The low apparent capacitance and the microlithographic processes for electrode design make tosylate an attractive material for future applications as an implantable biosensor for FSCV measurements. Additionally, the integration of tosylate electrodes on plastic substrates enables new electrochemical measurements at this polymer using FSCV.


Choosing an Advanced Therapy in Parkinson's Disease; is it an Evidence-Based Decision in Current Practice?
In advanced Parkinson's disease (PD), neurologists and patients face a complex decision for an advanced therapy. When choosing a treatment, the best available evidence should be combined with the professional's expertise and the patient's preferences. The objective of this study was to explore current decision-making in advanced PD. We conducted focus group discussions and individual interviews with patients (N = 20) who had received deep brain stimulation, Levodopa-Carbidopa intestinal gel, or subcutaneous apomorphine infusion, and with their caregivers (N = 16). Furthermore, we conducted semi-structured interviews with neurologists (N = 7) and PD nurse specialists (N = 3) to include the perspectives of all key players in this decision-making process. Data were analyzed by two researchers using a qualitative thematic analysis approach. Four themes representing current experiences with the decision-making process were identified: 1) information and information needs, 2) factors influencing treatment choice and individual decision strategies, 3) decision-making roles, and 4) barriers and facilitators to shared decision-making (SDM). Patient preferences were taken into account, however patients were not always provided with adequate information. The professional's expertise influenced the decision-making process in both positive and negative ways. Although professionals and patients considered SDM essential for the decision of an advanced treatment, they mentioned several barriers for the implementation in current practice. In this study we found several factors explaining why in current practice, evidence-based decision-making in advanced PD is not optimal. An important first step would be to develop objective information on all treatment options.


The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2α and ATF4 in Lung Cancer.
The expression of programmed death 1 (PD1) and programmed death ligand 1 (PDL1) can be induced by the interferon (IFN)/signal transducer and activator of transcription (STAT) pathway. The PD1/PDL1 reverse signaling can activate the eukaryotic translation initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4) pathway which in turn regulates the expression of IFN regulatory factor (IRF) 7 and IFNα. The eIF2α/ATF4 pathway is responsible for the integrated stress response (ISR) of unfolded protein response (UPR) which can affect immune cell function in tumor microenvironment. The protein levels of PDL1, IRF1, IRF7, STAT1, STAT2, IFNAR1, eIF2α, and ATF4 in the normal and tumor tissues of 27 subjects with lung cancer were determined by Western blot. The protein level of PDL1 was significantly correlated with those of IRF1, eIF2α, and ATF4 in the tissues of all subjects and the subgroup of squamous cell carcinoma but not in the normal tissue of adenocarcinoma. The protein levels of IRF1, eIF2α, and ATF4 were consistently correlated in the tumor tissues but to various extents in the normal ones. The protein level of PDL1 was not correlated with those of STAT1 and STAT2 in all the tissues. The PDL1 expression in lung cancer may be independent of STAT1 and STAT2. The PD1/PDL1 axis and UPR/ISR may be closely associated in the tumor tissues of lung cancer.


Cell biology of the presynaptic terminal.
The chemical synapse is a specialized intercellular junction that operates nearly autonomously to allow rapid, specific, and local communication between neurons. Focusing our attention on the presynaptic terminal, we review the current understanding of how synaptic morphology is maintained and then the mechanisms in synaptic vesicle exocytosis and recycling.


Allicin Induces Electrogenic Secretion of Chloride and Bicarbonate Ions in Rat Colon via the TRPA1 Receptor.
Allicin, an antioxidant from garlic, is known to regulate intestinal contractions, but its effect on intestinal ion transport is unclear. The aim of this study was to examine the role of allicin in the regulation of electrogenic ion transport in rat intestine by measuring the transmural potential difference (ΔPD). Allicin induced significant positive ΔPD, when administered to the serosal side of the colonic mucosal-submucosal preparation. Allicin-induced colonic ΔPD was largely diminished by incubation in the chloride-free solution, although the transient peak of ΔPD after application of allicin remained. This transient peak of ΔPD was significantly diminished in both the chloride- and the bicarbonate-free incubation solution. Induction of ΔPD by allicin was greatly diminished by AP-18, an inhibitor of the transient receptor potential (TRP) cation channel subfamily A member 1, TRPA1. Both alliin and S-allylcysteine, the analogues of allicin, had no effect on ΔPD and did not affect allicin-induced ΔPD in the colon. These results suggest that allicin mainly evokes the electrogenic chloride secretion and only partially increases the electrogenic bicarbonate secretion via TRPA1.


Urinary bactericidal activity of oral antibiotics against common urinary tract pathogens in an ex vivo model.
In this investigation, the urine samples obtained in a single oral-dose pharmacokinetic study were examined for their bactericidal activity against a range of relevant urinary tract pathogens. Six healthy volunteers received a single oral dose of ten oral antibiotics available in Croatia. Urine samples were taken every 2 h during the whole dosing interval of the particular antibiotic. The urinary bactericidal activity was tested by determination of urinary bactericidal titers. All antibiotics showed a significant urinary bactericidal activity against non-extended spectrum beta-lactamase Escherichia coli and Proteus mirabilis. Fluoroquinolones displayed high and persisting levels of urinary bactericidal activity against all gram-negative bacteria and Staphylococcus saprophyticus. Average urinary bactericidal activity can be predicted from in vitro susceptibility testing, but we expect that there will be patients with a low level of urinary bactericidal activity.


The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective.
Cushing's syndrome is considered a rare disease and its diagnosis can be challenging. Establishment of evidence-based recommendations is difficult. In 2008, several national and international consensus recommendations for the diagnosis or management of Cushing's syndrome were reported. The Endocrine Society, with the participation of the European Society of Endocrinology, has developed a task force to update recommendations for the diagnosis of Cushing's syndrome. The main aspects of these recommendations are presented in this article and discussed in the context of current research efforts in Europe focusing on the improvement of diagnosis and management of rare diseases including adrenal disorders such as Cushing's syndrome.


Smoking during pregnancy in relation to grandchild birth weight and BMI trajectories.
Maternal smoking has been linked to lower birth weight and higher risk of childhood obesity. However, it is unknown whether grand-maternal smoking during pregnancy is associated with grandchildren birth weight and body mass index (BMI) trajectories. We investigated associations of smoking during pregnancy with birth weight, risks of overweight and BMI trajectories among 46,858 mother-child dyads and 6,583 grandmother-mother-child triads of three cohort studies of related individuals. Smoking during pregnancy was reported by mothers, and anthropometric data were provided by participants in each cohort. Compared to grandchildren of non-smoking women, grandchildren of women who smoked more than 14 cigarettes per day throughout pregnancy were 70 g (95% CI: 12, 129 g; P for trend = 0.01) heavier at birth, and 18% (95% CI: 4%, 34%; P for trend = 0.01) more likely to become overweight. The mean BMI of grandchildren of women who smoked during pregnancy was 0.45 kg/m2 (95% CI: 0.14, 0.75 kg/m2; P for trend = 0.006) higher through adolescence and young adulthood than that of grandchildren of non-smoking mothers. Grandmothers' smoking during pregnancy was associated with higher birth weight, higher risk of overweight, and higher BMI through adolescence and young adulthood.


Quantifying the effect of light activated outer and inner retinal inhibitory pathways on glutamate release from mixed bipolar cells.
Inhibition mediated by horizontal and amacrine cells in the outer and inner retina, respectively, are fundamental components of visual processing. Here, our purpose was to determine how these different inhibitory processes affect glutamate release from ON bipolar cells when the retina is stimulated with full-field light of various intensities. Light-evoked membrane potential changes (ΔVm ) were recorded directly from axon terminals of intact bipolar cells receiving mixed rod and cone inputs (Mbs) in slices of dark-adapted goldfish retina. Inner and outer retinal inhibition to Mbs was blocked with bath applied picrotoxin (PTX) and NBQX, respectively. Then, control and pharmacologically modified light responses were injected into axotomized Mb terminals as command potentials to induce voltage-gated Ca2+ influx (QCa ) and consequent glutamate release. Stimulus-evoked glutamate release was quantified by the increase in membrane capacitance (ΔCm ). Increasing depolarization of Mb terminals upon removal of inner and outer retinal inhibition enhanced the ΔVm /QCa ratio equally at a given light intensity and inhibition did not alter the overall relation between QCa and ΔCm . However, relative to control, light responses recorded in the presence of PTX and PTX + NBQX increased ΔCm unevenly across different stimulus intensities: at dim stimulus intensities predominantly the inner retinal GABAergic inhibition controlled release from Mbs, whereas the inner and outer retinal inhibition affected release equally in response to bright stimuli. Furthermore, our results suggest that non-linear relationship between QCa and glutamate release can influence the efficacy of inner and outer retinal inhibitory pathways to mediate Mb output at different light intensities.


Effect of a monoclonal anti-lyt-1.1 on the functional activity of precursor, effector, and regulatory cells specific for murine alloantigens.
A monoclonal anti-Lyt-1.1 serum has been characterized in terms of its effect on various cell populations involved in cell-mediated immune responses. The monoclonal serum was compared to a conventionally prepared anti-Lyt-1.1 serum. Cytotoxic T cell precursors and effectors were found to be Lyt-1.1+. Helper T cells which participate in the induction of a cytotoxic response were also Lyt-1.1+ as were suppressor T cells which inhibit cytotoxic responses. The T cell that is required for the production of a nonspecific stimulatory factor, costimulator, and that has been shown to bear the same Ly markers as does the helper T cell, bears Lyt-1.1. Finally, the effector cell which mediates delayed-type hypersensitivity reactions to alloantigens has been shown to be Lyt-1.1+. In all of these cases treatment with the monoclonal anti-Lyt-1.1 and complement had the same effect as did treatment with a conventional anti-Lyt-1.1 and complement. The distribution of Lyt-1.1 on various cell types as determined using the monoclonal anti-Lyt-1.1 is in complete agreement with the Lyt-1.1 distribution obtained with conventional anti-Lyt-1.1 sera, and is quite different from the reactivity of an anti-Thy-1 serum as determined by strain distribution. The distribution of the Lyt-1.1 specificity on the T cells within a given strain is identical to that seen with the conventional anti-Lyt-1.1 serum and, as reported by many others, does not differ from the distribution of Thy-1 specificities.


The Introduction of Adult Appendicitis Score Reduced Negative Appendectomy Rate.
Implementation of a clinical risk score into diagnostics of acute appendicitis may provide accurate diagnosis with selective use of imaging studies. The aim of this study was to prospectively validate recently described diagnostic scoring system, Adult Appendicitis Score, and evaluate its effects on negative appendectomy rate. Adult Appendicitis Score stratifies patients into three groups: high, intermediate, and low risk of appendicitis. The score was implemented in diagnostics of adult patients suspected of acute appendicitis in two university hospitals. We analyzed the effects of Adult Appendicitis Score on diagnostic accuracy, imaging studies, and treatment. The study population was compared with a reference population of 829 patients suspected of acute appendicitis originally enrolled for the study of construction of the Adult Appendicitis Score. This study enrolled 908 patients of whom 432 (48%) had appendicitis. The score stratified 49% of all appendicitis patients into high-risk group with specificity of 93.3%. In the low-risk group, prevalence of appendicitis was 7%. The histologically confirmed negative appendectomy rate decreased from 18.2% to 8.7%, p<0.001, compared to the original dataset. Adult Appendicitis Score is a reliable tool for stratification of patients into selective imaging, which results in low negative appendectomy rate.


Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations.
Cardiopulmonary bypass (CPB) support is required in some lung transplantation (LTX) operations. CPB support and full-dose heparin increases the risks of bleeding and early graft dysfunction. We report our experiences of replacing CPB with heparin-bonded low-dose heparin extracorporeal membrane oxygenation (ECMO) support in LTX surgery. From 2003 to 2005 forty-seven patients were transplanted. Thirty-seven LTX patients were retrospectively evaluated for this study (10 patients were excluded due to heart-lung-, lung-kidney transplantation, LTX with bypass grafting, and ASD closure or emergency CPB support). Extracorporeal circulation support was necessary in 40% of the 37 LTX patients due to severe primary or secondary pulmonary hypertension (P or SPHTN), right heart dysfunction, or hemodynamic instability. There were seven LTX procedures with CPB and eight implantations with ECMO support. CPB (high-dose heparin) and ECMO support (ACT 160-220 s) was always set up through femoral veno-arterial canulation. All patients had limited access thoracotomies without transsection of the sternum. Normothermia was maintained in all patients. CPB patients: PPH 15%, COPD 15%, IPF with mean PAP>40 mmHg 70%. ECMO patients: PPH 13%, COPD 13%, IPF with severe PAP pressure elevation 74%. In patients undergoing LTX for PPH, the ECMO support was directly extended into the post-operative period. Packed red blood cell (PRBC) transfusion requirements during the operation and the first 24h were 13.25+/-1.6 PRBC units versus 5.1+/-2.8 PRBC units on CBP (p=0.02). Operative time was longer (p=0.11) in the ECMO LTX (451 min+/-76 vs 346+/-140). The increased 90-day mortality rate of the ECMO patients showed a trend toward significance (p=0.056), which was related to infectious complications (3 vs 1 patient). Severe graft ischemia/reperfusion injury occurred in 9% in the CPB versus 13% in the ECMO group. The 1-year survival was significantly reduced in ECMO patients (p=0.004, log-rank test). The advantages of femoral canulation rather than conventional central connections in lung transplantation procedures led to an undisturbed operative field. A significantly higher blood product amount was required in ECMO patients, which might lead to increased infection and mortality rates. CPB, obviously, should remain the standard support technique if extracorporeal circulation is required in lung transplantation surgery.


Intrasubject reliability of spinal range of motion and velocity determined by video motion analysis.
The purpose of this study was to investigate the repeatability of spinal range of motion (ROM) and movement velocity measurements of patients with chronic low back pain, using a two-dimensional motion analysis system. This apparatus uses reflective markers placed on anatomical landmarks and video digitization to derive ROM measurements from three segments of the spine and associated velocities through the respective ROMs. Forty-two patients with chronic LBP underwent ROM and movement velocity testing. Each subject was tested twice without removal of the markers to minimize error contribution from differences in marker placement. Results indicated that both the ROM measures and the velocity measures were highly repeatable. Intraclass correlations for the ROM measures ranged from .77 to .96. Velocity measures were also reliable, with intraclass correlation coefficients ranging from .75 to .97. Overall, the results seem to indicate that the video motion analysis system used in this study yields repeatable ROM and velocity measures on a clinical population. In practice, however, the measures may reflect greater errors due to the need of examiners to relocate markers at different testing sessions. These systems also offer distinct advantages over other means of obtaining ROM and velocity measures. The results of this study indicate that these measures may be obtained without undue concern for measurement artifact due to the instrumentation reliability.


Genome-Wide Epigenetic Regulation of Gene Transcription in Maize Seeds.
Epigenetic regulation is well recognized for its importance in gene expression in organisms. DNA methylation, an important epigenetic mark, has received enormous attention in recent years as it's a key player in many biological processes. It remains unclear how DNA methylation contributes to gene transcription regulation in maize seeds. Here, we take advantage of recent technologies to examine the genome-wide association of DNA methylation with transcription of four types of DNA sequences, including protein-coding genes, pseudogenes, transposable elements, and repeats in maize embryo and endosperm, respectively. The methylation in CG, CHG and CHH contexts plays different roles in the control of gene expression. Methylation around the transcription start sites and transcription stop regions of protein-coding genes is negatively correlated, but in gene bodies positively correlated, to gene expression level. The upstream regions of protein-coding genes are enriched with 24-nt siRNAs and contain high levels of CHH methylation, which is correlated to gene expression level. The analysis of sequence content within CG, CHG, or CHH contexts reveals that only CHH methylation is affected by its local sequences, which is different from Arabidopsis. In summary, we conclude that methylation-regulated transcription varies with the types of DNA sequences, sequence contexts or parts of a specific gene in maize seeds and differs from that in other plant species. Our study helps people better understand from a genome-wide viewpoint that how transcriptional expression is controlled by DNA methylation, one of the important factors influencing transcription, and how the methylation is associated with small RNAs.


Isolation and Characterization of EDAG-1, A Novel Gene Related to Regulation in Hematopoietic System.
A novel gene, named embryonic develop associated gene 1 ( EDAG -1) and abundantly expressed in human fetal liver tissues, was isolated by screening a human fetal liver cDNA library and the 5' RACE. The full length of EDAG-1 mRNA is 2 166 bp, with an open reading frame of 1 452 bp neucleotides, encoding a 484 amino acid protein. No domain or motif was found similar with other genes by Blast program. Two copies of AUUUA motif in 3' non-translated region show instability of its mRNA. The molecular weight of the protein is 55.3 kD identified by the translation in vitro. EDAG-1 is specifically expressed in hematopoietic tissues, and is quickly down-regulated during the differentiation of K562 cells induced by hemin and EPO. These results show that EDAG-1 is related to the regulation in hematopoietic system and the development of leukemia.


Use of steroids for self-enhancement: an epidemiologic/societal perspective.
Humans are basically competitive. For centuries, athletes have used various substances to enhance performance, increase strength, and prolong endurance. In the early 1940s, research indicating that testosterone improved a sense of well-being, appearance, and sexual performance led to the use of anabolic steroid hormones by a select few athletes. Today, even among high school students, the use of androgenic steroid hormones is prevalent, with 1% to 2% of adolescent girls and 4% to 6% of adolescent boys having used an anabolic steroid at least once. An estimated 1 million people in the United States are current of former users of anabolic-androgenic steroid hormones, with men having a higher prevalence of use than women. Androgenic steroid use has been associated with the use of other illicit drugs, cigarette smoking, and alcohol use. Nevertheless, anabolic-androgenic steroid hormones appear to have legitimate uses in certain patients. In HIV-infected, hypogonadal men, anabolic steroid hormones optimize muscle strength and muscle mass when combined with resistance exercise. Although a large number of people have used these drugs for many years, no studies of the long-term health effects have been done. However, when taken in supraphysiologic doses, these drugs are known to cause a wide range of acute adverse effects. When used in less then supraphysiologic doses in eugonadal or hypogonadal HIV-infected patients, these drugs reverse HIV-related hypogonadism, muscle wasting, and perhaps lipodystrophy. Provided that the oral preparations are not used and patients are closely monitored, anabolic-androgenic steroid hormones offer HIV-infected patients a better quality of life and an improved sense of well-being.


Transient hemodynamic instability caused by TIPS.
Variceal bleeding belongs to the one of the complications of portal hypertension and is a life-threatening condition. A transjugular intrahepatic portosystemic shunt (TIPS) is indicated in case of failure of the pharmacological and endoscopic therapy, even if it is associated with complications. Stent migration to the heart, is a rare event which may cause perforation of the right cardiac chambers or damage to the tricuspid valve. However, it may not be a problem in some cases. There are two approaches to extraction - percutaneous or surgical. Leaving the stent in situ is possible, especially in polymorbid patients. Choosing an optimal approach often requires interdisciplinary cooperation.


Regulation of blood coagulation factors XI and XII in patients with acute and chronic cerebrovascular disease: a case-control study.
Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.


Throwing injury of the elbow: assessment with gradient three-dimensional, fourier transform gradient-echo and short tau inversion recovery images.
We assessed MR findings of throwing injuries occurring in the elbow joint using three-dimensional Fourier transform (3DFT) and short tau inversion recovery (STIR) images. MR images of 63 elbows in 63 male patients aged from 10 to 32 years (mean age, 15 years 11 months) suffering from throwing injury were visually analyzed. The sequences used for the study were axial 3DFT and coronal STIR. Full-thickness tears were demonstrated in 34 elbows and undersurface tears of the ulnar collateral ligament (UCL) were demonstrated in five elbows. Thirty loose bodies were detected in 14 elbows. Cartilaginous damage due to osteochondral injury was depicted in 21 elbows. Multiplanar reformatted images using the 3DFT data set were useful for assessing torn UCLs, intraarticular loose bodies, and capitellar fragments. Full-thickness tears and undersurface tears of the UCL could be differentiated with STIR images. 3DFT and STIR sequences depict various aspects of throwing injuries occurring in the elbow.


Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.
This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. The range of AUA and Amax values in the study population overlapped that of historical control normal-weight subjects (<100 kg), indicating that weight-adjusted tinzaparin dosing yields a predictable response regardless of body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.


Polyamine-guided synthesis of anisotropic, multicompartment microparticles.
Colloidal particles that have nonuniform bulk or surface compositions are of emerging interest because of their potential applications involving advanced chemical storage and delivery and the self-assembly of novel functional materials. Experimental realization of anisotropic particles is much more difficult than that for particles with uniform bulk and surface composition, however. A new wet-chemical synthesis method to anisotropic microparticles is presented. This approach makes convenient use of the unusual observation of a salt-triggered separation of two water-solubilized polyamines into colloidal aggregates with nonuniform polymer composition. The anisotropic structure of these ionically cross-linked aggregates is explained by the difference in surface tensions of the contained single-polymer domains. Contacting the polymer aggregates with silicic acid or 13-nm silica nanoparticles leads to the charge-driven formation of solid or hollow microspheres, respectively. Depending on the poly(lysine)/poly(allylamine) ratio, the nonuniformity of the polymer aggregates translates to surface patches or internal compartments found in the resultant silica/polymer microparticles. Such hybrid materials with their unique structure could serve as a new basis for targeted chemical delivery and controlled release for potential applications in medicine, food, and cosmetics.


Role of cytosolic, tyrosine-insensitive prephenate dehydrogenase in Medicago truncatula.
l-Tyrosine (Tyr) is an aromatic amino acid synthesized de novo in plants and microbes downstream of the shikimate pathway. In plants, Tyr and a Tyr pathway intermediate, 4-hydroxyphenylpyruvate (HPP), are precursors to numerous specialized metabolites, which are crucial for plant and human health. Tyr is synthesized in the plastids by a TyrA family enzyme, arogenate dehydrogenase (ADH/TyrAa), which is feedback inhibited by Tyr. Additionally, many legumes possess prephenate dehydrogenases (PDH/TyrAp), which are insensitive to Tyr and localized to the cytosol. Yet the role of PDH enzymes in legumes is currently unknown. This study isolated and characterized Tnt1-transposon mutants of MtPDH1 (pdh1) in Medicago truncatula to investigate PDH function. The pdh1 mutants lacked PDH transcript and PDH activity, and displayed little aberrant morphological phenotypes under standard growth conditions, providing genetic evidence that MtPDH1 is responsible for the PDH activity detected in M. truncatula. Though plant PDH enzymes and activity have been specifically found in legumes, nodule number and nitrogenase activity of pdh1 mutants were not significantly reduced compared with wild-type (Wt) during symbiosis with nitrogen-fixing bacteria. Although Tyr levels were not significantly different between Wt and mutants under standard conditions, when carbon flux was increased by shikimate precursor feeding, mutants accumulated significantly less Tyr than Wt. These data suggest that MtPDH1 is involved in Tyr biosynthesis when the shikimate pathway is stimulated and possibly linked to unidentified legume-specific specialized metabolism.


Medical physics challenges in clinical MR-guided radiotherapy.
The integration of magnetic resonance imaging (MRI) for guidance in external beam radiotherapy has faced significant research and development efforts in recent years. The current availability of linear accelerators with an embedded MRI unit, providing volumetric imaging at excellent soft tissue contrast, is expected to provide novel possibilities in the implementation of image-guided adaptive radiotherapy (IGART) protocols. This study reviews open medical physics issues in MR-guided radiotherapy (MRgRT) implementation, with a focus on current approaches and on the potential for innovation in IGART.Daily imaging in MRgRT provides the ability to visualize the static anatomy, to capture internal tumor motion and to extract quantitative image features for treatment verification and monitoring. Those capabilities enable the use of treatment adaptation, with potential benefits in terms of personalized medicine. The use of online MRI requires dedicated efforts to perform accurate dose measurements and calculations, due to the presence of magnetic fields. Likewise, MRgRT requires dedicated quality assurance (QA) protocols for safe clinical implementation.Reaction to anatomical changes in MRgRT, as visualized on daily images, demands for treatment adaptation concepts, with stringent requirements in terms of fast and accurate validation before the treatment fraction can be delivered. This entails specific challenges in terms of treatment workflow optimization, QA, and verification of the expected delivered dose while the patient is in treatment position. Those challenges require specialized medical physics developments towards the aim of fully exploiting MRI capabilities. Conversely, the use of MRgRT allows for higher confidence in tumor targeting and organs-at-risk (OAR) sparing.The systematic use of MRgRT brings the possibility of leveraging IGART methods for the optimization of tumor targeting and quantitative treatment verification. Although several challenges exist, the intrinsic benefits of MRgRT will provide a deeper understanding of dose delivery effects on an individual basis, with the potential for further treatment personalization.


Pre-existing immunity to norovirus GII-4 virus-like particles does not impair de novo immune responses to norovirus GII-12 genotype.
Noroviruses (NoVs) are one of the leading causes of acute nonbacterial gastroenteritis in humans of all ages. In the 1990s, NoV genotype GII-4 became responsible for the majority of NoV sporadic gastroenteritis cases and outbreaks worldwide. Vaccine development against NoV GII-4 is underway. At the same time, there is concern of new emerging NoV genotypes, such as GII-12, which has been recently associated with increasing numbers of NoV outbreaks worldwide. The specific question is whether type-specific pre-existing immunity to NoV GII-4 might impair cognate immune response induced by new viral infections or vaccines. Using GII-4 and GII-12 virus-like particles, we tested the impact of the immunity generated against NoV GII-4 on de novo antibody responses to GII-12 in mice. We found that pre-existing immunity to NoV GII-4 did not impair de novo immune response to the novel antigen, therefore suggesting lack of original antigenic sin (OAS).


Utility of Trabecular Bone Score (TBS) in Bone Quality and Fracture Risk Assessment in Patients on Maintenance Dialysis.
Maintenance dialysis is associated with almost universal changes in bone metabolism collectively known as chronic kidney disease-mineral and bone disorder (CKD-MBD). These are accompanied in various proportions by bone loss and altered bone quality that led to an increased risk of fracture. Osteoporosis, age-related or postmenopausal, a condition that often coexists with CKD, is also a leading cause of fracture. Dual-energy X-ray densitometry (DXA) is the main tool for assessing the bone quantity and bone loss and the associated fracture risk. It has been validated in both CKD-MBD and osteoporosis. Trabecular bone score (TBS) is a DXA-derived algorithm for the evaluation of bone microarchitecture, and its clinical value has been repeatedly demonstrated in large cohorts of osteoporotic patients. However, its utility in patients on maintenance dialysis has not been conclusively shown. Published studies showed a lower TBS score and implicitly an altered bone microarchitecture in patients on maintenance dialysis, even after adjusting for various variables. Moreover, FRAX-based fracture risk is higher after adjusting for TBS, showing promise on an algorithm better estimating the clinical fracture risk in dialysis patients. However, TBS has not been demonstrated to independently predict clinical fractures in prospective studies on dialysis patients. Also, aortic calcifications and altered fluid balance could significantly affect TBS score and could hamper the widespread clinical use in patients on maintenance dialysis. In this mini-review, we focus on the benefits and pitfalls of TBS in the management of CKD-MBD and fracture risk assessment in patients on maintenance dialysis.


Getting the word out about treating borderline personality disorder: an online information resource.
This column reviews the need for greater awareness among mental health clinicians regarding evidence-based treatments for borderline personality disorder (BPD) and describes an online resource that has been developed to partially address this need. This resource is the Borderline Personality Disorder Clinician Resource Centre, which can be accessed at http://www.treatingBPD.ca.


Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.
Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.


Kinetics of Polymer Desorption from Colloids Probed by Aggregation-Induced Emission Fluorophore.
Polymer adsorption and desorption are fundamental in many industrial and biomedical applications. Here, we introduce a new method to monitor the polymer desorption kinetics in situ based on the behavior of aggregation-induced emission. Poly(ethylene oxide) and colloidal silica (SiO2) were used as a model system. It was found that the aggregation-induced emission method could be successfully used to determine the polymer desorption kinetics, and the polymer desorption followed the first-order kinetics. It was also found that the polymer desorption rate constant decreased with the increasing molecular weight, which could be described by a power law function kd ≈ M-0.28, close to that of the adsorption rate constant.


Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness.
Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.


Simplicity of condensed matter at its core: generic definition of a Roskilde-simple system.
The isomorph theory is reformulated by defining Roskilde-simple systems by the property that the order of the potential energies of configurations at one density is maintained when these are scaled uniformly to a different density. If the potential energy as a function of all particle coordinates is denoted by U(R), this requirement translates into U(Ra) < U(Rb) ⇒ U(λRa) < U(λRb). Isomorphs remain curves in the thermodynamic phase diagram along which structure, dynamics, and excess entropy are invariant, implying that the phase diagram is effectively one-dimensional with respect to many reduced-unit properties. In contrast to the original formulation of the isomorph theory, however, the density-scaling exponent is not exclusively a function of density and the isochoric heat capacity is not an exact isomorph invariant. A prediction is given for the latter quantity's variation along the isomorphs. Molecular dynamics simulations of the Lennard-Jones and Lennard-Jones Gaussian systems validate the new approach.