Malignant transformation in von recklinghausen disease in a rural farmer presenting as huge metastatic soft tissue chest wall tumour: a case report.
Although von Recklinghausen disease is relatively common at an incidence of 1 in 4000 live births, malignant transformation in a neurofibromatosis is quite rare estimated at about 5% therefore the importance of life-long follow up of all patients von Recklinghausen disease. This is a case report of a 45-year old Nigerian-Ibibio male farmer who presented with six months history of rapid growth in one of the numerous skin nodules which had been present since his teenage age. The clinical diagnosis of malignant change in von Recklinghausen's disease was confirmed by histopathologic examination of an incisional biopsy specimen. Radiological investigations also showed the metastatic status of the disease. The patient could not afford the cytotoxic chemotherapeutic agents prescribed. He therefore left the hospital and failed to return when a free-treatment voucher was ready for treatment in the following two days. He is assumed dead at home. Lifelong follow up for von Recklinghausen disease is emphasized to enable early detection of malignant change and also expansion of the national health insurance scheme to benefit the unemployed citizens.


Assessment of internal auditory canal tumors: a comparison of contrast-enhanced T1-weighted and steady-state T2-weighted gradient-echo MR imaging.
Although contrast-enhanced T1-weighted MR imaging is the standard of reference for diagnosing tumor in the cerebellopontine angle, high-resolution T2-weighted imaging may show more details of the seventh and eighth cranial nerve branches, resulting in more accurate tumor volume measurements. The purpose of this study was to compare two MR sequences for their ability to delineate internal auditory canal tumors. Twenty-seven ears in 21 patients with 16 confirmed schwannomas were studied with the 3D T2-weighted prototype segment-interleaved motion-compensated acquisition in steady state (SIMCAST) and the T1-weighted contrast-enhanced spoiled gradient-echo (SPGR) techniques. Twenty-eight axial sections were acquired using parameters of 17/3.3 (TR/TE), a 40 degrees flip angle, a 20 x 15-cm or 22 x 16-cm field of view (FOV), a 512 x 256 matrix, and a 0.4- or 1.2-mm section thickness for the SIMCAST technique, and 30/4.2, a 30 degrees flip angle, a 20 x 20-cm FOV, a 512 x 288 matrix, and a 1.5-mm section thickness for the SPGR technique. Tumor appearance and depiction of surrounding anatomy, including the cranial nerves, were evaluated. Tumor volumes were measured by manual tracing. Both sequences clearly identified tumors that ranged in size from 0.06 to 3.0 cm3. Measurements on both sequences agreed, on average, within 14%. The information from both sequences was complementary. SIMCAST usually delineated the CSF spaces better, whereas SPGR more clearly showed the tumor/brain boundary. SIMCAST and SPGR are suitable for tumor detection and volume measurements. SPGR has somewhat better contrast, but SIMCAST excels at depicting the surrounding anatomy and tumor involvement of the seventh and eighth cranial nerves.


Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex.
Disulfiram efficacy in treatment of cocaine addiction is attributed to the inhibition of dopamine-β-hydroxylase and reduction in brain noradrenaline (NA)/dopamine (DA) ratio. Using microdialysis, we investigated if disulfiram causes DA release from noradrenergic terminals and modifies cocaine-induced DA release. Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei, while it markedly increased DA not only in mPF but also in the occipital cortex, despite its scanty dopaminergic afferences, and modestly increased DA in the accumbens and caudate nuclei, despite their dense dopaminergic innervation. Disulfiram-induced DA accumulation was reversed in both cortices by tetrodotoxin infusion and by systemic administration of the α(2)-adrenoceptor agonist clonidine, but was not modified by the α(2)-adrenoceptor antagonist RS 79948 or the D(2)-like agonist quinpirole. Disulfiram prevented cocaine-induced NA release in the mPF cortex and nucleus accumbens, potentiated cocaine-induced DA release in the mPF cortex but failed to modify cocaine effect in the nucleus accumbens. DA release induced by disulfiram-cocaine combination in the mPF cortex was prevented by clonidine but not by quinpirole. We suggested that disulfiram, by removing NA-mediated inhibitory control on noradrenergic terminals, causes an unrestrained cocaine-induced DA release from those terminals in the mPF cortex. In the accumbens and caudate nuclei, "allogenic" DA concentration might be clouded by DA originated from dopaminergic terminals. The possible role of "allogenic" DA in disulfiram ability to prevent stress-induced reinstatement of cocaine seeking is discussed.


[Non-pharmacological management of hypertension in Southern Brazil].
A cross-sectional population-based study was carried out among individuals aged 20 to 69 years in the urban area of Pelotas, Rio Grande do Sul, Brazil. The objective was to analyze characteristics of hypertensive patients in relation to management of arterial hypertension. Among the 1,968 interviewees, 380 were hypertensive (19.3%), and 44.1% of these always consulted the same physician. Of the entire sample, 85.5% were sedentary, 48.2% showed excessive fat consumption, and 47.4% smoked. Most physicians recommend the following: lowering salt consumption (98.4%), cessation of alcohol consumption (93.7%), for losing weight, diet and consumption of low-fat food (88.2%), smoking cessation (73.2%), and physical activity (68.9%). The clinical management was classified as inadequate in 284 individuals (74.7%). Increased probability of adequate management was found among: women, individuals > 50 years, upper and middle-class patients, non-smokers, and patients with diabetes mellitus. Some findings showed positive aspects, but differences according to socioeconomic status evidenced lack of equity in care.


New techniques for the characterization of refuse-derived fuels and solid recovered fuels.
Solid recovered fuel (SRF) today refers to a waste-derived fuel meeting defined quality specifications, in terms of both origin (produced from non-hazardous waste) and levels of certain fuel properties. Refuse-derived fuel (RDF) nowadays is more used for unspecified waste after a basic processing to increase the calorific value and therefore this term usually refers to the segregated, high calorific fraction of municipal solid waste (MSW), commercial or industrial wastes. In comparison with conventional fuels, both types of secondary fuel show waste of inherently varying quality and an increased level of waste-specific contaminants.The transition from RDF to SRF in the emerging national and European market requires a quality assurance system with defined quality parameters and analytical methods to ensure reliable fuel characterization. However, due to the quality requirements for RDF and SRF, the current standardized analysis methods often do not meet these practical demands. Fast test methods, which minimize personnel, financial and time efforts and which are applicable for producers as well as users can be an important supporting tool for RDF- and SRF-characterization. Currently, a fast test system based on incineration and correlation analyses which enable the determination of relevant fuel parameters is under development. Fast test methods are not aimed at replacing current standardized test methods, but have to be considered as practical supporting tools for the characterization of RDF and SRF.


Live or Let Die?: Fine Margins Between Life and Death in a Brain-Dead Pregnancy.
In PP v Health Service Executive, the Irish High Court was recently asked to decide on the lawfulness of maintaining somatic treatment that was being provided to a brain-dead woman who was 15-weeks pregnant. In delivering judgment, Kearns P held that the treatment should not be maintained and that the artificial support being provided to the woman could lawfully be withdrawn. The legal basis for this ruling, however, is not free from criticism. The focus of this discussion is to consider how an English court would deal with a case similar to this should the need ever arise. There are crucial differences between English and Irish law which could impact upon the reasoning and, quite possibly, the outcome. Given that it is not beyond the realms of possibility that a similar case could occur in England at some point in the future, it is important that a number of legal questions are explored and their implications illuminated.


Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites.
Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism.


Four-wave mixing in nanosecond pulsed fiber amplifiers.
We present an experimental and theoretical analysis of four-wave mixing in nanosecond pulsed amplifiers based on double-clad ytterbium-doped fibers. This process leads to saturation of the amplified pulse energy at 1064 nm and to distortion of the spectral and temporal profiles. These behaviours are well described by a simple model considering both Raman and four-wave-mixing contributions. The role of seed laser polarization in birefringent fibers is also presented. These results point out the critical parameters and possible tradeoffs for optimization.


Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells.
The sodium iodide symporter (NIS), first identified in FRTL-5 cells, plays a critical role in iodide transport in the thyroid gland and in the production of the iodine-containing thyroid hormones. The aim of our study was to examine the regulation of NIS RNA steady-state levels and protein expression as well as functional activity in FRTL-5 cells. FRTL-5 cells cycling in media containing thyrotropin (TSH) were incubated for 48 hours with dexamethasone (10(-8)-10(-5) M), triiodothyronine (T3; 10(-9)-10(-6) M), methimazole (100 microM), propylthiouracil (PTU; 100 microM), perchlorate (10 microM) and potassium iodide (40 microM). In other experiments, cells were treated for 48 hours with various cytokines including interleukin-6 (IL-6) (100 U/mL), interferon-gamma (IFN-gamma) (100 U/mL), tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml), IL-1alpha (100 U/mL), and IL-1beta (100 U/mL). Northern blot analysis using a 32P-labeled rat NIS-specific cDNA probe (nucleotides 1397-1937) revealed NIS mRNA as a single species of approximately 3 kb. When normalized for beta-actin mRNA signal intensities, NIS RNA steady-state levels in viable FRTL-5 cells were suppressed by approximately 80% after incubation with dexamethasone and T3 in a concentration-dependent manner. Iodide accumulation was decreased by up to 40% after incubation with dexamethasone and T3, respectively, in a concentration-dependent manner. Using a rabbit polyclonal rNIS-specific antibody, Western blot analysis of FRTL-5 cell membranes revealed a 60% and 70% suppression of NIS protein expression after treatment with T3 (0.1 microM) and dexamethasone (1 microM), respectively. In additon, NIS RNA steady-state levels were decreased by approximately 50% after treatment of monolayers with methimazole, PTU, and potassium iodide, respectively. Incubation with methimazole and PTU resulted in a 20% and 25% decrease of iodide accumulation, respectively, whereas potassium iodide suppressed iodide accumulation by approximately 50%. Treatment of FRTL-5 cells with IL-6 and IL-1beta resulted in a 30% decrease of NIS RNA steady-state levels. IL-6 did not alter NIS functional activity, but IL-1beta suppressed iodide accumulation by approximately 25%. IFN-gamma and perchlorate failed to alter NIS RNA steady-state levels. In contrast to IFN-gamma that had no effect on iodide accumulation, perchlorate almost completely suppressed iodide accumulation. TNF-alpha and IL-1alpha failed to alter NIS RNA steady-state levels in higher passage numbers of FRTL-5 cells, whereas treatment with TNF-alpha and IL-1alpha of early passages of FRTL-5 cells (<20 cell passages) resulted in a 70% and 40% decrease of NIS RNA steady-state levels, respectively, and in a 20% suppression of NIS functional activity. In conclusion, our data suggest that various agents known to affect iodide transport are capable of differentially altering NIS gene expression and function in cultured thyroid cells. Suppression of NIS gene expression and function by certain cytokines may be responsible, at least in part, for the impaired radioiodine uptake by thyroid tissue in certain forms of thyroiditis.


Retracted: Effects of Vitamin K2 on Osteoporosis
The article entitled "Effects of Vitamin K2 on Osteoporosis, published in Curr Pharm Des 2004; 10(21): 2557-76, by Iwamoto J, Takeda T and Sato Y." has been retracted by the Editorial office of the journal Current Pharmaceutical Design, as the text, data and some figures used/referred in this review article are from sources which have been retracted or under investigation on the basis of data fabrication and falsification, authorship misconduct, duplicate publication, unethical research practices, text recycling/self-plagiarism, and unresolved concerns about data integrity and research conduct. The authors were informed of this complaint and were requested to give justification on the matter in their defense. However, no reply was received from their side in this regard. Some sources that have been retracted are as follows: 1. Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 2003; 44: 751-6. Available at: https://eymj.org/DOIx.php?id=10.3349/ymj.2019.60.1.115. 2. Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998; 23: 291-6. Available at: https://www.sciencedirect.com/science/article/pii/S8756328298001082. 3. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. Bone 2002; 31: 114-8. Available at: https://pubmed.ncbi.nlm.nih.gov/ 12110423/. Bentham Science apologizes to its readers for any inconvenience this may have caused. The Bentham Editorial Policy on Article. Retraction can be found at https://benthamscience.com/editorial-policies-main.php It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.


[Problem of noise as an ecologic factor on urban territories].
The authors evaluated levels of transport noise in intensive automobile traffic of Ust-Kamenogorsk. Noise on traffic area appeared to spread not only onto the area nearing the road, but deeply into housing blocks. Thus, the area exposed to the most severe noise covers blocks and districts situated along highways of citywide importance. Reasons of high noise level are: blocks and districts are not isolated from noise passing from highways, greenery planting is insufficient, most territories intended for recreation and children playgrounds are used for traffic.


The use of the case-crossover design in studying illicit drug use.
The case-crossover design was developed to study time-varying exposures that cause transient excess risk of acute health events. It is a variant of case-control and subject-as-own-control research designs, involving use of information about exposure history of each case to estimate the transient effect. This kind of self-control design can help to reduce sampling bias otherwise introduced in the selection of controls, as well as confounding bias that might be derived from enduring individual characteristics, especially personality traits and other long-standing inherited or acquired vulnerabilities. When the subject is used as his or her own control, these personal vulnerabilities are matched. In this paper we discuss strengths and weaknesses of the case-crossover design and suggest applications of the case-crossover design in epidemiologic studies on suspected hazards of illicit drug use, and in studies of drug use and co-occurring psychiatric disturbances. We conclude that the case-crossover design can play a useful role, but it discloses a need to secure fine-grained measurements in epidemiologic research on psychiatric comorbidity. As explained in the paper, we also believe the case-crossover method may be of use to criminologists who study the drugs-crime nexus, to services researchers and clinicians who seek to understand treatment entry and compliance behavior, and to etiologists interested in polydrug use.


Diastolic and autonomic dysfunction in early cirrhosis: a dobutamine stress study.
OBJECTIVE. Presence of cardiac dysfunction in patients with advanced cirrhosis is widely accepted, but data in early stages of cirrhosis are limited. Systolic and diastolic functions, dynamics of QT-interval, and pro-atrial natriuretic peptide (pro-ANP) are investigated in patients with early stage cirrhosis during maximal β-adrenergic drive. MATERIAL AND METHODS. Nineteen patients with Child A (n = 12) and Child B cirrhosis (n = 7) and seven matched controls were studied during cardiac stress induced by increasing dosages of dobutamine and atropine. RESULTS. Pharmacological responsiveness was similar in cirrhosis and controls and the heart rate (HR) increased by 66 ± 15 versus 67 ± 8 min(-1). HR-blood pressure product increased equally by 115% in both cirrhotic patients and controls. However, time to resume HR of 100 beats/min was significantly longer in cirrhosis, p < 0.01. The QTc interval increased after dobutamine infusion in cirrhosis (0.41 ± 0.02 vs. 0.43 ± 0.02 s, p = 0.001) but similar electrophysiological changes were seen in controls. Cardiac volumes increased with the severity of disease. The increased cardiac output was primarily attributed to increased stroke volume. The ejection fraction was similar in patients and controls. Peak filling rate was longer in cirrhosis compared to controls (1.8 ± 0.4 and 1.4 ± 0.2 end-diastolic volume/s, p < 0.01). Pro-ANP was higher in cirrhosis and increased during stress by 13% compared to 0% in controls, p < 0.01. CONCLUSIONS. These findings indicate that patients with early stage cirrhosis exhibit early diastolic and autonomic dysfunction as well as elevated pro-ANP. However, the cardiac chronotropic and inotropic responses to dobutamine stress were normal. The dynamics of ventricular repolarization appears normal in patients with early stage cirrhosis.


Comparison of conventional versus real-time PCR detection of Brugia malayi DNA from dried blood spots from school children in a low endemic area.
Microscopic detection of active phase of lymphatic filariasis is indicated by the presence of microfilaria in whole blood. This method is not sensitive and requires relatively large amount of blood sample. PCR allows very sensitive detection of the parasite DNA using a smaller amount of blood; and the use of dried blood spots facilitates sample transportation. Nevertheless, limited studies have been reported on PCR using dried blood spot for detection of Brugia malayi. In this study, we investigated the effects of concentrating whole blood genomic DNA sample and the amplification methods [conventional PCR (C-PCR) and real-time PCR] on the detection of B. malayi DNA from dried blood spots from a very low endemic area in Malaysia. Both C-PCR and real-time PCR detected 2 out of 18 (11%) samples as positive from non-concentrated genomic DNA preparations. After the DNA samples were pooled and concentrated, both C-PCR and realtime PCR detected B. malayi DNA amplifications in 7 out of 18 (39%) samples. However one sample which showed faint band in C-PCR was detected as highly positive in real-time PCR. In conclusion, both C-PCR and real-time PCR using dried blood spots from a low endemic area demonstrated equal sensitivity for detection of B. malayi DNA.


Infectious arthritis in the neonate caused by Haemophilus influenzae.
Two newborns had hematogenous pyarthrosis due to Haemophilus influenzae. One infant had signs of sepsis and dactylitis involving several fingers and toes. She also developed a soft tissue abscess, meningitis, and a septic hip, and was found to be infected with a nontypable organism. In the second infant, a shoulder traumatized at birth became infected with a type b strain. In both cases, the patients were successfully treated, but delays occurred in selecting the optimal therapeutic agent because of failure to appreciate that Haemophilus may cause systemic infection in the newborn. In the first infant the source of the infection was identified as the mother's endocervical canal. This patient is also of interest because in contrast to previous reports of Haemophilus infection in the newborn, bactericidal activity was present in the maternal serum.


New transcutaneous jaundice device with two optical paths.
To confirm the accuracy and precision of transcutaneous bilirubin (TcB) values measured by a new device with two optical paths (JM-103) and the value of total serum bilirubin (TSB) level in clinical units of measurement. For comparison of the levels of accuracy and precision of JM-103 and the old device (JM-102), serum samples were collected from 77 Japanese infants in three different hospitals including 24 preterm infants and 53 term infants. Measurement of TcB by JM-103 and JM-102 were performed on the forehead of each infant within 30 min before or after blood sampling. The range of TSB was limited to 19.6 mg/dL and to 17 mg/dL for preterm infants. The correlation coefficients for all subjects (r = 0.94) and for term and preterm subjects between TcB measured by JM-103 and TSB was higher than that between TcB measured by JM-102 and TSB. The regression line in term infants between TcB measured by JM-103 and TcB was similar to that in preterm infants. The error distribution of TcB measured by JM-102 and TSB for all subjects (0.00 +/- 2.21) and for term and preterm subjects was larger than that of TcB measured by JM-103 and TSB (all subjects, 0.30 +/- 1.55).


Ribosomal DNA sequences of Glugea anomala, G. stephani, G. americanus and Spraguea lophii (Microsporidia): phylogenetic reconstruction.
The microsporidian species Glugea anomala, G. stephani, G. americanus and Spraguea lophii were compared by using sequence data derived from their small subunit rDNA genes which were amplified by polymerase chain reaction and directly sequenced. These sequence data and published data of G. atherinae were analyzed and were used to infer a phylogenetic tree. The 5 microsporidian fish parasites appeared to be closely related. The higher sequence similarities demonstrated among G. anomala, G. stephani and G. atherinae suggest that these 3 parasites are in fact only 1 species of Glugea. Moreover, the higher sequence similarities between S. lophii and G. americanus support the transfer of the latter Glugea species into the genus Spraguea.


Biosurfactant coated silver and iron oxide nanoparticles with enhanced anti-biofilm and anti-adhesive properties.
Pseudomonas aeruginosa and Staphylococcus aureus are among the hazardous biofilm forming bacteria ubiquitous in industrial/clinical wastes. Serious efforts are required to develop effective strategies to control surface-growing antibiotic resistant pathogenic bacterial communities which they are emerging as a global health issue. Blocking hazardous biofilms would be a useful aspect of biosurfactant coated nanoparticles (NPs). In this regard, we report a facile method for the synthesis of rhamnolipid (RL) coated silver (Ag) and iron oxide (Fe3O4) NPs and propose the mechanism of their synergistic antibacterial and anti-adhesive properties against biofilms formed by P. aeruginosa and S. aureus. These NPs demonstrated excellent anti-biofilm activity not only during the biofilms formation but also on the pre-formed biofilms. Mechanistically, RL coated silver (35 nm) and Fe3O4 NPs (48 nm) generate reactive oxygen species, which contribute to the antimicrobial activity. The presence of RLs shell on the nanoparticles significantly reduces the cell adhesion by modifying the surface hydrophobicity and hence enhancing the anti-biofilm property of NPs against both mentioned strains. These findings suggest that RL coated Ag and Fe3O4 NPs may be used as potent alternate to reduce the infection severity by inhibiting the biofilm formation and, therefore, they possess potential biomedical applications for antibacterial coatings and wound dressings.


Setting resource utilization standards in a Community Mental Health Center.
Recognizing the impediments to standard setting in community mental health centers, the utilization review (UR) committee at West-Ros-Park Mental Health Center in Boston based its UR standards on clients' ability or inability to meet social and personal expectations in four areas: productivity, independent living/self-care, immediate social relationships, and extended social networks. Classifying treatment modalities into four service categories and analyzing clients' disabilities enabled the UR committee to establish practical standards for appropriate amounts and duration of services based on clients' role performance scores. Implications of this standard-setting approach are discussed, and an example of the standard-setting process undertaken in one of the facility's treatment programs is described.


Identification and validation of early genetic biomarkers for apple replant disease.
Apple replant disease (ARD) is a serious threat to producers of apple trees and fruits worldwide. The ARD etiology is not unraveled and managing options are either economically not applicable or environmentally harmful. Thus, interest is given in biomarkers that allow to indicate ARD situations at early time points in order to classify soils according to ARD severity but also to analyze the effectiveness to potential countermeasures. This study aimed at (i) identifying ARD biomarkers on the transcriptional level in root tissue by analyzing the expression of previously identified candidate genes in ARD soils of different origin and texture and (ii) testing the specificity of these marker genes to ARD. In vitro propagated M26 plantlets were submitted to a bio-test with three ARD soils, either untreated or disinfected by γ-irradiation. Expression of seven candidate genes identified in a previous transcriptomic study was investigated by RT-qPCR in a time course experiment. Already three days after planting, a prominent upregulation of the phytoalexin biosynthesis genes biphenyl synthase 3 (BIS3) and biphenyl 4-hydroxylase (B4Hb) was observed in the untreated ARD variants of all three soils. The phytoalexin composition in roots was comparable for all three soils and the total phytoalexin content correlated with the expression of BIS3 and B4Hb. The third promising candidate gene that was upregulated under ARD conditions was the ethylene-responsive transcription factor 1B-like (ERF1B). In a second experiment M26 plantlets were exposed to different abiotic stressors, namely heat, salt and nutrient starvation, and candidate gene expression was determined in the roots. The expression levels of BIS3 and B4Hb were highly and specifically upregulated in ARD soil, but not upon the abiotic stress conditions, whereas ERF1B also showed higher expression under heat stress. In conclusion, BIS3 and B4Hb are recommended as early ARD biomarkers due to their high expression levels and their high specificity.


Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications.
A set of yeast strains based on Saccharomyces cerevisiae S288C in which commonly used selectable marker genes are deleted by design based on the yeast genome sequence has been constructed and analysed. These strains minimize or eliminate the homology to the corresponding marker genes in commonly used vectors without significantly affecting adjacent gene expression. Because the homology between commonly used auxotrophic marker gene segments and genomic sequences has been largely or completely abolished, these strains will also reduce plasmid integration events which can interfere with a wide variety of molecular genetic applications. We also report the construction of new members of the pRS400 series of vectors, containing the kanMX, ADE2 and MET15 genes.


A Population-Based Twin Study of Childhood Irritability and Internalizing Syndromes.
Childhood irritability exhibits significant theoretical and empirical associations with depression and anxiety syndromes. The current study used the twin design to parse genetic and environmental contributions to these relationships. Children ages 9-14 from 374 twin pairs were assessed for irritability and symptoms of depression, generalized anxiety, panic, social phobia, and separation anxiety using dimensional self-report instruments. Multivariate structural equation modeling decomposed the correlations between these syndromes into genetic and environmental components to examine shared and specific risk domains. Irritability had significant associations with each internalizing symptom domain. Genetic contributions to irritability are moderately correlated with genetic risk for symptoms of depression, generalized anxiety, and separation anxiety with weaker overlap with the other anxiety syndromes. Familial and specific environmental risk factors explained covariation among syndromes and indicated potential syndrome-specific risk. There is substantial overlap among the genetic and environmental factors that influence individual differences in irritability and those that increase liability for depression and anxiety symptoms in children. These findings deepen the current understanding of childhood internalizing risk factors and provide important implications for syndrome prediction and susceptibility gene discovery efforts.


Biochemical analysis of Thermotoga maritima GH36 alpha-galactosidase (TmGalA) confirms the mechanistic commonality of clan GH-D glycoside hydrolases.
Organization of glycoside hydrolase (GH) families into clans expands the utility of information on catalytic mechanisms of member enzymes. This issue was examined for GH27 and GH36 through biochemical analysis of GH36 alpha-galactosidase from Thermotoga maritima (TmGalA). Catalytic residues in TmGalA were inferred through structural homology with GH27 members to facilitate design of site-directed mutants. Product analysis confirmed that the wild type (WT) acted with retention of anomeric stereochemistry, analogous to GH27 enzymes. Conserved acidic residues were confirmed through kinetic analysis of D327G and D387G mutant enzymes, azide rescue, and determination of azide rescue products. Mutation of Asp327 to Gly resulted in a mutant that had a 200-800-fold lower catalytic rate on aryl galactosides relative to the WT enzyme. Azide rescue experiments using the D327G enzyme showed a 30-fold higher catalytic rate compared to without azide. Addition of azide to the reaction resulted in formation of azide beta-d-galactopyranoside, confirming Asp327 as the nucleophilic residue. The Asp387Gly mutation was 1500-fold catalytically slower than the WT enzyme on p-nitrophenyl alpha-d-galactopyranoside. Analysis at different pH values produced a bell-shaped curve of the WT enzyme, but D387G exhibited higher activity with increasing pH. Catalyzed reactions with the D387G mutant in the presence of azide resulted in formation of azide alpha-d-galactopryanoside as the product of a retaining mechanism. These results confirm that Asp387 is the acid/base residue of TmGalA. Furthermore, they show that the biochemical characteristics of GH36 TmGalA are closely related to GH27 enzymes, confirming the mechanistic commonality of clan GH-D members.


Wurtzite AlN(0001) Surface Oxidation: Hints from Ab Initio Calculations.
With superior electrical and thermal properties, aluminum nitride (AlN) exhibits wide application. However, AlN is rather oxygen-sensitive and tends to be oxidized at high temperature. The surface oxidation of AlN remains a major challenge, while the underlying physics of AlN surface oxidation is still elusive. Here, First-principles calculations were performed to study wurtzite AlN(0001) surface oxidation process. The adsorption energy of oxygen was calculated to be site-dependent on the surface with varying O coverage. Calculation indicates that oxygen atoms are preferentially adsorbed at the hollow site (H3) of the AlN(0001) surface regardless of the O coverage. N2 is determined as the dominant gas product. The procedure of N3- removal and the formation of N vacancies (VN) take place step by step. VN plays an accelerating role in the oxidation of AlN, and O2- prefers to occupy the site of VN via consuming the Al p lone-pair electrons and passivating the dangling bond states of Al. An O-Al-O layer is formed when the first Al-N bilayer is fully oxidized, which could be regarded as a precursor of γ-Al2O3. On the basis of our atomic-level simulation, a possible phase transformation mechanism from γ-Al2O3 to α-Al2O3 was further proposed.


Chronic illness, disability, and mental and social well-being: findings of the Ontario Child Health Study.
Chronic childhood illness, disability, and psychosocial problems are receiving major attention in current pediatric care. Much of the evidence associating chronic physical problems and mental health and adjustment problems has come from clinic-based studies and is often inconsistent in its conclusions. This paper reports the findings of the Ontario Child Health Study, an epidemiologic survey of 3,294 children 4 to 16 years of age in the general community, concerning the relationship of psychiatric disorders and social adjustment problems among children with chronic illness, medical conditions, and long-term disability in contrast to children free of chronic physical health problems. Age- and sex-adjusted risks for psychiatric disorders and social problems, compared with those for healthy peers, were calculated: children with both chronic illness and associated disability were at greater than threefold risk for psychiatric disorders and considerable risk for social adjustment problems. Children with chronic medical conditions, but no disability, were at considerably less risk: about a twofold increase in psychiatric disorders but little increased risk for social adjustment problems was observed. A relative underuse of specialized mental health services by children who might benefit supports the opinion that all physicians in the community who care for children with chronic health problems should become skilled in the recognition of existing or incipient mental health and social problems and familiar with preventive and treatment approaches that may lessen the excessive burden of psychosocial problems among those with chronic ill-health.


Integrated Systems Biology Analysis of Transcriptomes Reveals Candidate Genes for Acidity Control in Developing Fruits of Sweet Orange (Citrus sinensis L. Osbeck).
Organic acids, such as citrate and malate, are important contributors for the sensory traits of fleshy fruits. Although their biosynthesis has been illustrated, regulatory mechanisms of acid accumulation remain to be dissected. To provide transcriptional architecture and identify candidate genes for citrate accumulation in fruits, we have selected for transcriptome analysis four varieties of sweet orange (Citrus sinensis L. Osbeck) with varying fruit acidity, Succari (acidless), Bingtang (low acid), and Newhall and Xinhui (normal acid). Fruits of these varieties at 45 days post anthesis (DPA), which corresponds to Stage I (cell division), had similar acidity, but they displayed differential acid accumulation at 142 DPA (Stage II, cell expansion). Transcriptomes of fruits at 45 and 142 DPA were profiled using RNA sequencing and analyzed with three different algorithms (Pearson correlation, gene coexpression network and surrogate variable analysis). Our network analysis shows that the acid-correlated genes belong to three distinct network modules. Several of these candidate fruit acidity genes encode regulatory proteins involved in transport (such as AHA10), degradation (such as APD2) and transcription (such as AIL6) and act as hubs in the citrate accumulation gene networks. Taken together, our integrated systems biology analysis has provided new insights into the fruit citrate accumulation gene network and led to the identification of candidate genes likely associated with the fruit acidity control.


[Adjuvant therapy with elemental diet in chronic inflammatory intestinal diseases. Comparative study].
26 in-patients (17 with Crohn's disease, 9 with ulcerative colitis) were given high-molecular (diet 1; 12 patients) or low-molecular (diet 2; 14 patients) elemental diets (6.3-12.6 MJ) additional to drug treatment previously given as out-patients. The activity index fell on both diets (on diet 1 from 253 to 83; diet 2 from 259 to 86), stool frequency decreased (on diet 1 from 7.1 to 0.9 per day; diet 2 from 5.6 to 2.0 per day), as did blood sedimentation rate (diet 1 from 57/80 to 30/51 mm; diet 2 from 56/80 to 23/45 mm). Body-weight, total protein, albumin and red blood corpuscles were not changed significantly. There was no significant difference between the two diet groups. The results raise the question of whether low-molecular elemental diet enriches the treatment of chronic inflammatory disease.


Ontogeny of rat hepatic adrenoceptors.
Hepatic alpha-1, alpha-2 and beta-2 adrenoceptors were characterized during development of the rat through Scatchard analysis of [3H]prazosin, [3H]rauwolscine and [125I]pindolol binding to liver membrane preparations. Major changes in adrenoceptor numbers occur shortly before birth at weaning. The fetal rat liver is characterized by a large number of alpha-2 adrenoceptors, which falls 10-fold by birth. The number of hepatic beta-2 adrenoceptors decreases gradually during development, and is lower at all times than the number of alpha-1 and alpha-2 adrenoceptors. The developmental profile of the hepatic alpha-1 adrenoceptor is biphasic: there is a 2 to 3-fold fall in alpha-1 adrenoceptor number at birth and a 3- to 5-fold rise at weaning. While absolute numbers of alpha-1 and beta-2 adrenoceptors do not correlate precisely with reported actions of epinephrine and norepinephrine on hepatic metabolism during ontogeny, the increasing ratio of alpha-1/beta-2 hepatic adrenoceptors may contribute to the conversion from predominantly beta effects of catecholamines reported in fetal and suckling rat liver to the predominantly alpha-1 effects that are well documented in the adult male rat.


CT enterography and fistulizing Crohn's disease: clinical benefit and radiographic findings.
To estimate the clinical benefit of CT enterography (CTE) in patients with fistulizing Crohn's disease and describe the appearance of fistulas at CTE. Crohn's patients who had undergone CTE, which diagnosed an abscess or fistula, were identified. A gastroenterologist reviewed clinical notes prior to and following CTE to assess the pre-CTE clinical suspicion for fistula/abscess, and post-CTE alteration in patient management. A radiologist reassessed all fistula-positive cases, which were confirmed by a non-CT reference standard, to describe their radiologic appearance. Fifty-six patients had CT exams identifying 19 abscesses and 56 fistulas. There was no or remote suspicion of fistula or abscess at pre-imaging clinical assessment in 50% of patients. Thirty-four patients (61%) required a change in or initiation of medical therapy and another 10 (18%) underwent an interventional procedure based on CT enterography findings. Among 37 fistulas with reference standard confirmation, 30 (81%) were extraenteric tracts, and 32 (86%) were hyperenhancing compared to adjacent bowel loops. Most fistulas (68%) contained no internal air or fluid. CTE detects clinically occult fistulas and abscesses, resulting in changes in medical management and radiologic or surgical intervention. Most fistulas appear as hyperenhancing, extraenteric tracts, usually without internal air or fluid.


Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation.
Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.


Does a facultative precocious life cycle predispose the marine trematode Proctoeces cf. lintoni to inbreeding and genetic differentiation among host species?
Intraspecific variability in parasite life cycle complexity (number of hosts and species of hosts in the life cycle) may have an impact how parasite genetic variation is partitioned among individual parasites, host individuals or host species within a given area. Among digenean trematodes, a three-host life cycle is common. However, a few species are precocious and may reach sexual maturity in what is typically regarded as the second intermediate host. The objective of this study was to determine whether a precocious life cycle predisposes digeneans to possible inbreeding or genetic subdivision among host species. As a study system, we used the digenean Proctoeces cf. lintoni whose metacercariae precociously mature (facultative) without a cyst wall in the gonads of multiple sympatric species of keyhole limpets (Fissurella spp.), typically regarded as the second intermediate hosts. Genotyped parasites were collected from four species of limpets and the clingfish Sicyases sanguineus, the third and final host where sexual maturity occurs. We found very high microsatellite diversity, Hardy-Weinberg equilibrium over all genotyped individuals, and little to no genetic structuring among parasites collected from the different host species. The fact that metacercariae do not encyst in the keyhole limpets, coupled with the high mixing potential of an aquatic environment, likely promote panmixia in local populations of P. cf. lintoni.


[Which language will MEDLINE speak in the next millennium?].
To analyze the trends in the prevalence of the languages used in Medline, since its creation up to the present time, for the overall indexed articles in this database and those specifically related to the field of Urology. The results are extrapolated to determine the trend over the next 15 years. The Pubmed page on Internet (http:www.nlm.nih.gov/pubs/factsheets/nlm. html) and the Medline database (OldMedline 1960-1965 and current Medline 1966-1999) were accessed to determine the total number of indexed articles and the distribution by year, language and country. The same method was applied for articles specifically pertaining to the field of Urology. Overall, English accounts for 75% of the nearly 10 million articles indexed in Medline since its creation. The prevalence of the English language has grown steadily since 1966 when it already accounted for 53% of these indexed articles up to 89% in 1999, for a yearly increase of 1%. Similar results were found for the articles specifically pertaining to the field of Urology. The number of the indexed articles in the English language has grown to almost 400% since 1966, whereas those written in other languages have dropped by 40%. In some countries like Holland, Germany or Japan, most of the articles are published in English. If the current trend continues, all the articles indexed in the Medline database will comprise only those written in the English language by 2014.


Current Research and New Perspectives of Telemedicine in Chronic Heart Failure: Narrative Review and Points of Interest for the Clinician.
This is a narrative review of both the literature and Internet pertaining to telemedicine projects within the field of heart failure, with special attention placed on remote monitoring of second-generation projects and trials, particularly in France. Since the beginning of the 2000's, several telemedicine projects and trials focused on chronic heart failure have been developed. The first telemedicine projects (e.g., TEN-HMS, BEAT-HF, Tele-HF, and TIM-HF) primarily investigated telemonitoring or for the older ones, telephone follow-up. Numerous second-generation telemedicine projects have emerged in Europe over the last ten years or are still under development for computer science heart failure, especially in Europe, such as SCAD, OSICAT, E-care, PRADO-INCADO, and TIM-HF2. The E-care telemonitoring project fits within the telemedicine 2.0 framework, based on connected objects, new information and communication technologies (ICT) and Web 2.0 technologies. E-care is the first telemedicine project including artificial intelligence (AI). TIM-HF2 is the first positive prospective randomized study with regards to EBM with positive significant clinical benefit, in terms of unplanned cardiovascular hospital admissions and all-cause deaths. The potential contribution of second-generation telemedicine projects in terms of mortality, morbidity, and number of hospitalizations avoided is currently under study. Their impact in terms of health economics is likewise being investigated, taking into account that the economic and social benefits brought up by telemedicine solutions were previously validated by the original telemedicine projects.


Spectral properties and retinal distribution of ferret cones.
The spectral mechanisms of the ferret (Mustela putorious furo) were studied with electroretinogram (ERG) flicker photometry. Variations in adaptation state and flicker rate were used to define corneally based spectral sensitivities for the three classes of receptor present in the retina of this mustelid-rods (lambdamax = 505 nm), S cones (430 nm), and L cones (558 nm). The retinal distributions of the two classes of cone were determined using opsin antibody labeling. Ferret retinas contain a total of about 1.3 million cones with L cones outnumbering S cones in a ratio of approximately 14:1. ERGs were also recorded using 18.75-Hz flickering stimuli that were designed to isolate signals from individual cone classes. The contrast/response functions for signals originating from both S and L cones were linear over low-to-moderate levels of contrast, but with greatly different slopes for the two cone types. The L:S contrast gain ratio derived from a comparison of these slopes, as well as inferences drawn from another experiment in which responses to various combinations of L- and S-cone activation were analyzed, suggest that contributions of these two cone types to the flicker ERG have a relative weighting of about 4:1 to 5:1 (L/S).


Polyproline as a Minimal Antifreeze Protein Mimic That Enhances the Cryopreservation of Cell Monolayers.
Tissue engineering, gene therapy, drug screening, and emerging regenerative medicine therapies are fundamentally reliant on high-quality adherent cell culture, but current methods to cryopreserve cells in this format can give low cell yields and require large volumes of solvent "antifreezes". Herein, we report polyproline as a minimum (bio)synthetic mimic of antifreeze proteins that is accessible by solution, solid-phase, and recombinant methods. We demonstrate that polyproline has ice recrystallisation inhibition activity linked to its amphipathic helix and that it enhances the DMSO cryopreservation of adherent cell lines. Polyproline may be a versatile additive in the emerging field of macromolecular cryoprotectants.


The use of endocavitary irradiation for selected carcinomas of the rectum: ten years experience.
Since July, 1973, endocavitary irradiation has been used to treat 129 patients with rectal carcinoma. The lesion must be a modified Dukes' A, well-differentiated adenocarcinoma and no more than 5 cm in diameter and within 12 cm of the anal verge. Specialized diagnostic techniques assist with the clinical selection. Specially designed proctoscopes are used to visualize the carcinoma which is treated by a Philips RT-50 contact machine. 11000-12000 cGy are delivered in four treatments administered at 2-3 weekly intervals. No systemic side effects have been observed and local morbidity is minimal. This treatment preserves the anal sphincter, and sexual function in male patients. Hospitalization is not required and there is no risk of mortality. Recurrence has been observed in six of 129 patients within 18 months of treatment for known reasons. Two of these six patients have died from disease and a further 25 from other causes. The local control rate is 95.3%. This treatment modality has been offered also to 87 patients for palliation and this has been effectively obtained in 82.7%. This technique is an alternative to surgery in selected cases.


Odds of transfusion for older adults compared to younger adults undergoing surgery.
Recent randomized controlled trials have shown no benefit for transfusion to a hemoglobin >10 g/dL compared with lower hemoglobin thresholds in the perioperative period, even among older adults. Nevertheless, physicians may choose to transfuse older adults more liberally than younger adults. It is unclear whether older patients have higher odds than younger patients of being transfused in the perioperative period. Our objective in this study was to determine whether the odds of transfusion are higher in older patients than in younger patients in the perioperative period. We conducted this retrospective observational cohort study at a tertiary care academic medical center. We included adults who had undergone a surgical procedure as an inpatient at our institution from January 2010 to February 2012. The primary analysis compared the odds of transfusion for patients >65 years old with the odds of transfusion in younger patients based on multilevel multivariable logistic regression analyses including adjustment for comorbidities, surgical service, lowest in-hospital hemoglobin value, gender, and estimated surgical blood loss and accounted for clustering by the surgeon and procedure. We included 20,930 patients in this analysis. In multilevel models adjusted for comorbidities, surgical service, estimated surgical blood loss, and lowest in-hospital hemoglobin value, with surgeon and procedure as random effects, patients > 65 years old had 62% greater odds (odds ratio, 1.62; 95% confidence interval, 1.40-1.88; P < 0.0001) of being transfused than did younger patients. When patients were stratified by lowest in-hospital hemoglobin (7.00-7.99, 8.00-8.99, 9.00-9.99, and ≥10.00 g/dL), the odds of transfusion generally increased with each additional decade of age in every stratum, except for that containing patients in whom the lowest in-hospital hemoglobin did not decrease below 10 g/dL. When the odds of transfusion were compared between younger and older patients, significant differences were observed among surgical services (P = 0.02) but not among anesthesia specialty divisions (P = 0.9). Older adults have greater odds of receiving red blood cell transfusion in the perioperative period than do younger patients, despite the lack of evidence supporting higher hemoglobin triggers in elderly patients. Further research is needed to determine whether transfusion practice in the elderly is an opportunity for education to improve blood management.


Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects.
Adenovirus-mediated gene therapy holds significant potential especially for applications requiring high levels of target tissue transduction. While significant advances in clinical adenoviral gene therapy applications have been made in cancer, the clinical translation of adenoviral gene replacement therapy for genetic disease has lagged. Encouragingly, advances in vector production have led to the development of Helper-Dependent ("gutted" or "high capacity") adenoviral vectors (HDV) deleted of all viral coding genes. HDV significantly reduces the chronic toxicity associated with early generation adenoviral vectors that has been most significant after systemic administration in both small and large animal models. However, the field remains confounded by innate immune responses inherent to adenovirus, and more generally, to the adaptive immune response to transgene. Together they decrease the effective therapeutic index for any particular treatment. This review summarizes the current advances toward understanding the decisive cell and molecular mechanisms underlying the acute toxicity to systemic HDV administration. We focus on the complex immune response and consequences of systemic vector delivery in the context of liver-directed monogenic disease therapy. Future development of interventions to avoid the innate immune response, including vector and pharmacologic manipulations, should further contribute to minimizing vector toxicity while maximizing the efficacy of systemic HDV gene transfer.


Profiling of T Cell Repertoire in SARS-CoV-2-Infected COVID-19 Patients Between Mild Disease and Pneumonia.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.


Upregulation of Glutamatergic Receptors in Hippocampus and Locomotor Hyperactivity in Aged Spontaneous Hypertensive Rat.
Epidemiologic studies have indicated that chronic hypertension may facilitate the progression of abnormal behavior, such as emotional irritability, hyperactivity, and attention impairment. However, the mechanism of how chronic hypertension affects the brain and neuronal function remains unclear. In this study, 58-week-old male spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats were used. Their locomotor activity and neuronal function were assessed by the open field test, novel object, and Y maze recognition test. Moreover brain tissues were analyzed. We found that the aged SHR exhibited significant locomotor hyperactivity when compared to the WKY rats. However, there was no significant difference in novel object and novel arm recognition between aged SHR and the WKY rats. In the analysis of synaptic membrane protein, the expression of glutamatergic receptors, such as the N-methyl-D-aspartate (NMDA) receptor receptors subunits 2B (GluN2B) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 1 (GluA1) in the hippocampus of SHR were significantly higher than those of WKY rats. In addition, in the synaptic membrane of SHR's hippocampus and medial prefrontal cortex (mPFC), a down-regulation of astrocytes was found, though the excitatory amino acid transporter 2 (EAAT2) remained constant. Moreover, a down-regulation of microglia in the hippocampus and mPFC was seen in the SHR brain. Long-term exposure to high blood pressure causes upregulation of glutamate receptors. The upregulation of glutamatergic receptors in hippocampus may contribute to the hyper-locomotor activity of aged rodents and may as a therapeutic target in hypertension-induced irritability and hyperactivity.


When color helps.
To reduce the inappropriate identification of eye drops, through the use of different colors. A group of 34 healthy volunteers was presented to two groups of four eye drops each. All eye drops were placed in identical, unlabelled vials. In one group, all four eye drops were transparent. In the other group, each had a different color. A number was assigned to each eye drop, and the volunteer was asked to identify it by color. We measured the correct index in the identification of the eye drops of the two groups. The volunteers had a level of education from incomplete junior school to complete graduate course, with 16 males (48%) and 18 females (52%), age range of 21 to 87 years. The success rate in the group of colored eye drops was 88% and, in the group of transparent, 24%. The use of colorings in eye drops can help distinguishing the vials and preventing misidentification.


Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA).
Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival. In this USA multicentre population-based study, case participants (diagnosed during 1993-1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively. Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29-0.66) and OES (OR=0.43, 95% CI=0.26-0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42-0.95) and modestly for OEA (HR=0.87, 95% CI=0.60-1.26), but CIs were wide. Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.


Human environment conference: citizen advisers muddle through.
An article in Science (29 October, page 479) which alluded critically to a political appointee to a State Department environmental advisory committee, incorrectly identified the appointee as Mrs. Bruce B. Benson, president of the League of Women Voters. Science regrets the error and any injury done to Mrs. Benson's reputation and that of the League, and recognizes that they play respected roles in many governmental issues.


Cyclin T1-dependent genes in activated CD4 T and macrophage cell lines appear enriched in HIV-1 co-factors.
HIV-1 is dependent upon cellular co-factors to mediate its replication cycle in CD4(+) T cells and macrophages, the two major cell types infected by the virus in vivo. One critical co-factor is Cyclin T1, a subunit of a general RNA polymerase II elongation factor known as P-TEFb. Cyclin T1 is targeted directly by the viral Tat protein to activate proviral transcription. Cyclin T1 is up-regulated when resting CD4(+) T cells are activated and during macrophage differentiation or activation, conditions that are also necessary for high levels of HIV-1 replication. Because Cyclin T1 is a subunit of a transcription factor, the up-regulation of Cyclin T1 in these cells results in the induction of cellular genes, some of which might be HIV-1 co-factors. Using shRNA depletions of Cyclin T1 and transcriptional profiling, we identified 54 cellular mRNAs that appear to be Cyclin T1-dependent for their induction in activated CD4(+) T Jurkat T cells and during differentiation and activation of MM6 cells, a human monocytic cell line. The promoters for these Cyclin T1-dependent genes (CTDGs) are over-represented in two transcription factor binding sites, SREBP1 and ARP1. Notably, 10 of these CTDGs have been reported to be involved in HIV-1 replication, a significant over-representation of such genes when compared to randomly generated lists of 54 genes (p value<0.00021). The results of siRNA depletion and dominant-negative protein experiments with two CTDGs identified here, CDK11 and Casein kinase 1 gamma 1, suggest that these genes are involved either directly or indirectly in HIV-1 replication. It is likely that the 54 CTDGs identified here include novel HIV-1 co-factors. The presence of CTDGs in the protein space that was available for HIV-1 to sample during its evolution and acquisition of Tat function may provide an explanation for why CTDGs are enriched in viral co-factors.


Protective effect of crocin on gentamicin-induced nephrotoxicity in rats.
Gentamicin is used for the treatment of Gram-negative bacterial infections. However, gentamicin administration is limited because of nephrotoxicity. The aim of the present study was to evaluate the protective effect of crocin against gentamicin-induced nephrotoxicity in rats. Thirty two male Wistar rats received gentamicin (100 mg/kg, IP), with or without crocin (100 mg/kg, IP) for seven consecutive days. Plasma creatinine and urea-nitrogen concentrations, oxidative stress and histopathological changes of kidney tissues were monitored. Administration of gentamicin resulted in significant increases in plasma creatinine and urea-nitrogen concentrations and renal tissue malondialdehyde (MDA) level, and a decrease in the renal tissue ferric reducing/antioxidant power (FRAP) level. Crocin decreased plasma creatinine and urea-nitrogen concentrations and tissue MDA level, but increased the level of tissue FRAP. In addition, gentamicin led to cellular damages including glomerular atrophy, cellular desquamation, tubular necrosis and fibrosis, epithelial oedema of proximal tubules, perivascular edema, vascular congestion and intra-tubular proteinaceous casts, all of which were partially recovered by crocin. Crocin has protective effects against functional disturbances, oxidative stress and tissue damages induced by gentamicin.


Impact of Establishing a Pain Clinic in a Rural Cancer Centre Based on the Knowledge and Experience of the Pain of Cancer Patients - A Prospective, Questionnaire-Based Study.
Unrelieved pain significantly affects the quality of life of cancer patients. In rural settings, cancer patients do not have information or knowledge about how to control their pain because of a lack of resources or awareness. We conducted an interventional, questionnaire-based prospective study in a rural tertiary care oncological centre to look for the impact of establishing a pain clinic based on the knowledge and experience of cancer patients regarding their cancer pain. The patient pain questionnaire was filled by 380 random non-surgical patients complaining of pain who visited our centre for the treatment of cancer. The information generated was used for setting up a pain clinic covering all aspects of cancer pain. After 3 months of starting the pain clinic services, all these patients who visited the pain clinic at least once were again surveyed similarly. Out of 380 patients, we could only follow up with 348 patients and other patients were lost to follow-up. After visiting the pain clinic the mean value of the response for most of the questions decreased suggesting that the responses became more favourable as the knowledge improved and the experience of the pain became less distressing for the patients. The mean value of the responses to all the questions related to the overall knowledge of cancer pain before visiting a pain clinic was 4.22 ± 1.58 and after visiting a pain clinic was 3.83 ± 0.95 which was statistically significant (P = 0.000). The mean value of the responses to the questions related to the overall experience of the pain before visiting the pain clinic was 3.81 ± 1.42 and after visiting the pain clinic was 2.14 ± 1.05 which was highly significant (P = 0.000). We found out that the patients who had a higher mean value of the responses (8-10) suggesting the most unfavourable responses benefitted the most and the number of patients having the most unfavourable responses decreased after visiting the pain clinic. In a rural tertiary healthcare cancer centre, the establishment of a pain clinic increased the general understanding and experience of cancer patients regarding their pain and pain management.


Knowledge, personal risk and experiences of HIV/AIDS among people with disabilities in Swaziland.
Although there has been research focused on the disabling consequences of HIV/AIDS, there has been very little documented information about HIV/AIDS for individuals with disability prior to infection. There is evidence to suggest that people with disabilities face inequalities in accessing health information and services. The aim of this study was to explore whether disabled and non-disabled young adults in Swaziland perceive HIV/AIDS similarly. A qualitative study using focus-group discussions was conducted. Four focus groups were conducted with a total of 56 non-disabled adults (aged 16-29 years) and four focus groups were conducted with a total of 32 adults with either a physical or hearing disability (aged 18-32 years). The focus-group schedule explored knowledge about HIV/AIDS, personal risk and experiences of health-seeking practices. Information and awareness about HIV/AIDS was good in both rural and urban areas among the non-disabled participants, who obtained their information from a wide range of sources. In contrast, participants with disability, who obtained information about HIV/AIDS from a limited range of sources, lacked knowledge about HIV/AIDS and were misinformed about modes of transmission. Women with disabilities described experiences of sexual exploitation and abuse, which was perceived to be higher among disabled women than their non-disabled peers; they felt this was because disabled women were perceived to be 'free' from the HIV virus by non-disabled men. Further research is necessary to enable HIV/AIDS programmes to address the specific needs of people with disabilities.


Accumulation of amino acids by the perfused rat liver in the presence of ethanol.
1. The rate of gluconeogenesis from alanine in the perfused rat liver is affected by the presence of other metabolizable substances, especially fatty acids, ornithine and ethanol. Gluconeogenesis is accelerated by oleate and by ornithine. When both oleate and ornithine were present the acceleration was greater than expected on the basis of mere additive effects. 2. Much NH(3) and some urea were formed from alanine when no ornithine was added. With ornithine almost all the nitrogen released from alanine appeared as urea. 3. Lactate was a major product of alanine metabolism. Addition of oleate, and especially of oleate plus ornithine, decreased lactate formation. 4. Ethanol had no major effect on gluconeogenesis from alanine when this was the sole added precursor. Gluconeogenesis was strongly inhibited (87%) when oleate was also added, but ethanol greatly accelerated gluconeogenesis when ornithine was added together with alanine. 5. In the absence of ethanol the alanine carbon and alanine nitrogen removed were essentially recovered in the form of glucose, lactate, pyruvate, NH(3) and urea. 6. In the presence of ethanol the balance of both alanine carbon and alanine nitrogen showed substantial deficits. These deficits were largely accounted for by the formation of aspartate and glutamine, the formation of which was increased two- to three-fold. 7. When alanine was replaced by lactate plus NH(4)Cl, ethanol also caused a major accumulation of amino acids, especially of aspartate and alanine. 8. Earlier apparently discrepant results on the effects of ethanol on gluconeogenesis from alanine are explained by the fact that under well defined conditions ethanol can inhibit, or accelerate, or be without major effect on the rate of gluconeogenesis. 9. It is pointed out that in the synthesis of urea through the ornithine cycle half of the nitrogen must be supplied in the form of asparate and half in the form of carbamoyl phosphate. The accumulation of aspartate and other amino acids suggests that ethanol interferes with the control mechanisms which regulate the stoicheiometric formation of aspartate and carbamoyl phosphate.


How effective in your training of volunteers?
This work addresses one of the basic concepts of volunteer management, a three-level program for training volunteers. The author addresses the need for an appropriate amount of training, the important categories of training for volunteers and the use of volunteers as trainers of other volunteers. She presents a perspective of training of volunteers which is applicable to many types of organizations utilizing volunteers and to a diversity of volunteer services. The author's direct and simple approach to this aspect of volunteer management serves as a reminder of the important part training plays in the volunteer experience.


Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.
The heightened interest in pain management is making the need for appropriate boundary setting within the clinician-patient relationship even more apparent. Unfortunately, it is impossible to determine before hand, with any degree of certainty, who will become problematic users of prescription medications. With this in mind, a parallel is drawn between the chronic pain management paradigm and our past experience with problems identifying the "at-risk" individuals from an infectious disease model. By recognizing the need to carefully assess all patients, in a biopsychosocial model, including past and present aberrant behaviors when they exist, and by applying careful and reasonably set limits in the clinician-patient relationship, it is possible to triage chronic pain patients into three categories according to risk. This article describes a "universal precautions" approach to the assessment and ongoing management of the chronic pain patient and offers a triage scheme for estimating risk that includes recommendations for management and referral. By taking a thorough and respectful approach to patient assessment and management within chronic pain treatment, stigma can be reduced, patient care improved, and overall risk contained.


Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial.
This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild-to-moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2-week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (-45.94% vs -32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigator's global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (-37.5% vs -6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted.


Beyond clinical outcomes: Case control study of the role of race in disruptive life events for people with serious mental illness.
To understand how race and serious mental illness (SMI) interact for disruptive life events defined as financial (bankruptcy and judgement filings), and non-financial (arrests). Patients were adults with schizophrenia (SCZ; N = 16,159) or bipolar I disorder (BPI; N = 30,008) matched 1:1 to patients without SMI (non-SMI) from health systems in Michigan and Southern California during 1/1/2007 through 12/31/2018. The main exposure was self-reported race, and the outcome was disruptive life events aggregated by Transunion. We hypothesized that Black patients with SCZ or BPI would be the most likely to experience a disruptive life event when compared to Black patients without SMI, and all White or Asian patients regardless of mental illness. Black patients with SCZ had the least likelihood (37% lower) and Asian patients with BPI had the greatest likelihood (2.25 times higher) of experiencing a financial disruptive life event among all patients in the study. There was no interaction of race with either SCZ or BPI for experiencing an arrest. The findings did not support our hypotheses for patients with SCZ and partially supported them for patients with BPI. Clinical initiatives to assess social determinants of health should consider a focus on Asian patients with BPI.


Altered renal expression of Na(+) transporters and ROMK in protein-deprived rats.
Potassium depletion has been associated with altered sodium reabsorption in tubule segments. We studied if the altered abundance of Na(+) transporters and ROMK are associated with distal potassium secretion that contributes to the development of hypokalemia in protein-deprived rats. After weaning, Wistar rats were fed with a low-protein diet (8%, LP) for 14 days and then recovered with a normal-protein (NP) diet (24%, RP). An age-matched control group was fed with an NP diet (24%, NP). We showed hypokalemia, lower glomerular filtration rate and higher FEK(+) in the LP group. Immunoblotting revealed that the type 3 Na(+)/H(+) exchanger in the cortex was decreased in the LP group. However, the type 2 Na(+)-K(+)-2Cl(-) cotransporter was increased in the outer stripe of the outer medulla in the LP group. The abundance of the aldosterone-regulated Na(+)-Cl(-) cotransporter (NCC) and epithelial Na(+) channel (ENaC) was higher in the LP group and was associated with higher plasma aldosterone level. ROMK protein levels were increased. Na(+)/K(+)-ATPase protein levels were the same in both groups. After the recovery period, the expression of Na(+) transporters and ROMK returned to control values. We conclude that increased expression of NCC, ENaC subunits, and ROMK contributed to distal potassium secretion leading to enhanced potassium excretion, which may explain the hypokalemia resulting from LP feeding. A role of aldosterone may be suggested.


Inpatient cardiac rehabilitation soon after hospitalization for acute decompensated heart failure: a propensity score study.
Postdischarge management of acute decompensated heart failure (ADHF) remains an ongoing challenge. We sought to assess whether inpatient cardiac rehabilitation (CR) soon after hospitalization for ADHF improves outcome. Patients (N = 275) hospitalized for ADHF were enrolled. The primary outcome was a composite of all-cause mortality and urgent heart transplantation (UHT) at 1 year. The followup started at the time of discharge from the acute care setting. Because of the observational nature of the study, a propensity score analysis was used to predict the likelihood of undergoing CR. A multivariable Cox regression analysis adjusted for propensity score was used to assess the effect of CR on the primary outcome. Of the 275 patients, 130 underwent CR. Among the baseline variables of the index hospitalization for ADHF, propensity score derivation identified male gender, New York Heart Association Class IV, refractory HF, moderate to severe mitral or tricuspid regurgitation, nonuse of renin-angiotensin-aldosterone system inhibitors, and daily dosage of furosemide, as being independently associated with the likelihood of undergoing CR. No patient was lost to followup. During the 12-month followup, 74 patients died and 3 underwent UHT. The overall incidence of the primary outcome was 28%. On propensity score-adjusted Cox multivariable analysis, the relative risk of the primary outcome for participants in CR compared with nonparticipants in CR was 0.58 (confidence interval [CI]: 0.34-0.99; P = .04). Results suggest that the strategy of inpatient CR soon after discharge from the acute care setting improves 1-year UHT-free survival of patients with ADHF.


Metagenomic Assembly and Prokaryotic Metagenome-Assembled Genome Sequences from the Northern Gulf of Mexico "Dead Zone".
Coastal regions experiencing declining dissolved oxygen are increasing in number and severity around the world. However, despite the importance of microbial metabolism in coastal hypoxia, few metagenomic surveys exist. Our data set from within the second largest human-caused hypoxic region provides opportunities to more deeply explore the microbiology of these systems.


Mucoadhesive cellulosic derivative sponges as drug delivery system for vaginal application.
Vaginal delivery of active drugs has been largely studied for local and systemic applications. It is well known that vagina is a complex route, due to physiological and non-physiological changes. Therefore, in order to achieve a prolonged local effect, these variations have to be considered. The aim of this study was to formulate and to characterize a solid system, called sponges, obtained by lyophilization of cellulosic derivative (HEC 250M) hydrogels. These sponges have to meet particular criteria to be adapted for vaginal application: they have to adhere to the vaginal cavity and to be rehydrated by the small amount of vaginal fluids. Moreover, they have to be easily manipulated and to be stable. Three freezing temperatures have been tested to prepare sponges (-15°C, -25°C, -35°C). By SEM analyzes, it was observed that the pores into the sponges were smaller and numerous as the freezing temperature decreases. However, this temperature did not have any influence on the rehydration speed that was rather influenced by the HEC concentration. Viscosity and mucoadhesive strength of hydrogels and corresponding sponges were also measured. It appeared that these parameters are mainly dependent on the HEC concentration. These mucoadhesive sponges can be considered as potential drug delivery systems intended for vaginal application.


Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells.
After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.


Linear growth in preschool children treated with mass azithromycin distributions for trachoma: A cluster-randomized trial.
Mass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children. 24 rural Ethiopian communities that had received biannual mass azithromycin distributions over the previous four years were enrolled in a parallel-group, cluster-randomized trial. Communities were randomized in a 1:1 ratio to either continuation of biannual oral azithromycin (20mg/kg for children, 1 g for adults) or to no programmatic antibiotics over the 36 months of the study period. All community members 6 months and older were eligible for the intervention. The primary outcome was ocular chlamydia; height and weight were measured as secondary outcomes on children less than 60 months of age at months 12 and 36. Study participants were not masked; anthropometrists were not informed of the treatment allocation. Anthropometric measurements were collected for 282 children aged 0-36 months at the month 12 assessment and 455 children aged 0-59 months at the month 36 assessment, including 207 children who had measurements at both time points. After adjusting for age and sex, children were slightly but not significantly taller in the biannually treated communities (84.0 cm, 95%CI 83.2-84.8, in the azithromycin-treated communities vs. 83.7 cm, 95%CI 82.9-84.5, in the untreated communities; mean difference 0.31 cm, 95%CI -0.85 to 1.47, P = 0.60). No adverse events were reported. Periodic mass azithromycin distributions for trachoma did not demonstrate a strong impact on childhood growth. The TANA II trial was registered on clinicaltrials.gov #NCT01202331.


Stability of molecular dynamics simulations of classical systems.
The existence of a shadow Hamiltonian H̃ for discrete classical dynamics, obtained by an asymptotic expansion for a discrete symplectic algorithm, is employed to determine the limit of stability for molecular dynamics (MD) simulations with respect to the time-increment h of the discrete dynamics. The investigation is based on the stability of the shadow energy, obtained by including the first term in the asymptotic expansion, and on the exact solution of discrete dynamics for a single harmonic mode. The exact solution of discrete dynamics for a harmonic potential with frequency ω gives a criterion for the limit of stability h ≤ 2/ω. Simulations of the Lennard-Jones system and the viscous Kob-Andersen system show that one can use the limit of stability of the shadow energy or the stability criterion for a harmonic mode on the spectrum of instantaneous frequencies to determine the limit of stability of MD. The method is also used to investigate higher-order central difference algorithms, which are symplectic and also have shadow Hamiltonians, and for which one can also determine the exact criteria for the limit of stability of a single harmonic mode. A fourth-order central difference algorithm gives an improved stability with a factor of 3, but the overhead of computer time is a factor of at least two. The conclusion is that the second-order "Verlet"-algorithm, most commonly used in MD, is superior. It gives the exact dynamics within the limit of the asymptotic expansion and this limit can be estimated either from the conserved shadow energy or from the instantaneous spectrum of harmonic modes.


Inwardly rectifying potassium channels in the regulation of vascular tone.
Potassium ion (K+) channel activity is one of the major determinants of vascular muscle cell membrane potential and thus vascular tone. Four types of K+ channels are functionally important in the vasculature-Ca(2+)-activated K+ (KCa) channels, voltage-dependent K+ (Kv) channels, ATP-sensitive K+ (KATP) channels, and inwardly rectifying K+ (KIR) channels, and the latter type will be the subject of this review. Recent advances in vascular KIR channel research indicate that this channel: 1) is present in vascular muscle; 2) modulates basal arterial tone; 3) mediates powerful hyperpolarization and vasodilator responses to small but physiological increases in extracellular K+; 4) may contribute to vasodilatation in response to flow-induced shear stress; 5) may be inhibited by protein kinase C activity; 6) may be involved in vasorelaxation mediated by endothelium-derived hyperpolarizing factor; and 7) may be functionally altered in cardiovascular diseases. Vascular effects of KIR channels have so far been most extensively studied in the cerebral circulation where KIR function may be important in coupling cerebral metabolism and blood flow.


1.52-GHz micromechanical extensional wine-glass mode ring resonators.
Vibrating polysilicon micromechanical ring resonators, using a unique extensional wine-glass-mode shape to achieve lower impedance than previous UHF resonators, have been demonstrated at frequencies as high as 1.2 GHz with a Q of 3,700, and 1.52 GHz with a Q of 2,800. The 1.2-GHz resonator exhibits a measured motional resistance of 1 MOmega with a dc-bias voltage of 20 V, which is 2.2 times lower than the resistance measured on radial contourmode disk counterparts at the same frequency. The use of larger rings offers a path toward even lower impedance, provided the spurious modes that become more troublesome as ring size increases can be properly suppressed using methods described herein. With spurious modes suppressed, the high-Q and low-impedance advantages, together with the multiple frequency on-chip integration advantages afforded by capacitively transduced micromechanical resonators, make this device an attractive candidate for use in the front-end RF filtering and frequency generation functions needed by wireless communication devices.


Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.
Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post-stent implantation. Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima. A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling. Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.


Bowline, a novel protein localized to the presomitic mesoderm, interacts with Groucho/TLE in Xenopus.
Cells in the prospective somite of Xenopus laevis embryos rotate in an orchestrated manner to form a segregated somite. The prospective somite boundaries are prepatterned by gene expressions in the unsegmented presomitic mesoderm (PSM). However, the roles of polarized gene expression in this boundary formation are not well elucidated. Here we identified a novel gene, bowline, which localizes to the anterior halves of S-II, III in the PSM of X. laevis. Bowline associated with corepressor XGrg-4, a Xenopus homolog of Groucho/TLE protein. A WRPW tetrapeptide motif in Bowline was prerequisite for coprecipitation with XGrg-4 and for downregulation of X-Delta-2 by bowline RNA injection. This study indicates that Bowline is a novel protein interacting with Groucho/TLE and may play a role in somitogenesis in X. laevis.


Proviral deletions and oncogene base-substitutions in insertionally mutagenized c-myc alleles may contribute to the progression of avian bursal tumors.
Bursal lymphomas induced in chickens by avian leukosis viruses (ALVs) harbor proviral insertions that augment expression of an adjacent cellular oncogene, c-myc. To analyze such insertionally mutagenized c-myc genes in greater detail, we isolated molecular clones from two independent tumors. Precise proviral integration has occurred within the transcribed region of the c-myc gene in both mutant alleles. The proviruses bear different internal deletions that preclude the expression of the gag, pol, and env genes. The c-myc gene from bursal lymphoma LL4 contains a single copy of an ALV long terminal repeat (LTR), presumably the product of homologous recombination between LTRs at the ends of a normal provirus; the "solo" LTR is positioned in the correct orientation to act as a promoter for the c-myc gene. Bursal lymphoma LL3 contains an ALV provirus positioned upstream in the opposite transcriptional orientation to the coding exons of c-myc and deleted from a site within the leader region into the gag gene. In addition, the nucleotide sequence of the c-myc gene from tumor LL3 differs from the published sequence of the normal c-myc coding region at 3 positions of 180 determined. One of these changes, a silent nucleotide transition, is documented as a somatic mutation by restriction endonuclease mapping. It is flanked by two other candidate tumor-specific point mutations, one of which predicts an amino acid replacement, Pro----Thr at position 63. Thus, additional lesions that may affect the expression of viral genes and the quantity and nature of the putative c-myc gene product occur in provirally mutated c-myc alleles and may contribute to tumor progression.


On the inhibitory effect of Drynaria fortunei extract on human myeloma SP20 cells.
The objective of the study was to investigate the inhibitory effect of Drynaria fortunei extract on human myeloma SP2 cells. Three different total extracts of Drynaria fortunei were obtained by reflux extraction method using different organic solvents including ethanol, methanol and petroleum ether. Their anticancer activities on SP20 cells were tested, and the maximum inhibition rate was obtained. The inhibitory effects on tumour cells at 12 h, 24 h, 36 h and 48 h were tested, and the inhibition curves at different time periods were plotted. The results showed that the methanol and ethanol extracts have similar inhibition rates at 24 h, which are around 55%. On the other hand, the maximum inhibition rate of petroleum ether extract is only 36% within 24 h. Moreover, within the time periods of 36 h and 48 h, its inhibition rates are all below 10%.