bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrosative stress causes amino acid auxotrophy in hmp mutant Salmonella Typhimurium
Authors: Park Yoon Mee , Park Hee Jeong , Joung Young Hee , Bang Iel Soo
Published: July 2011

Cytotoxic nitic oxide (NO) damages various bacterial macromolecules, resulting in abnormal metabolism by mechanisms largely unknown. We show that NO can cause amino acid auxotrophy in Salmonella Typhimurium lacking major NO‐metabolizing enzyme, flavohemoglobin Hmp. In NO‐producing cultures, supplementation with amino acid pool restores growth of Hmp‐deficient Salmonella to normal growth phases, whereas excluding Cys or BCAA Leu, Ile, or Val from amino acid pool reduces growth recovery. Data suggest that, without detoxification, NO might inactivate key enzymes in the biosynthesis pathway of amino acids essential for Salmonella replication in amino acid‐limiting host environments.
Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology
Authors: Talaat A. , Brinkmann D. , Dhundee J. , Hana Y. , Bevan J. , Irvine R. , Bailey S. , Woolas R.
Published: July 2011

A. Talaat, D. Brinkmann, J. Dhundee, Y. Hana, J. Bevan, R. Irvine, S. Bailey and R. Woolas  Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology

Objective:  To review the risk of pre‐invasive and invasive gynaecological pathology in women referred with cervical cytology reporting ?glandular neoplasia.

Methods:  Review of the case notes of all women referred with cervical cytology reported as ?glandular neoplasia between January 1999 and December 2008 at two UK hospitals: Portsmouth Hospitals NHS Trust and Queen Mary’s Hospital Sidcup. The category of ‘borderline nuclear change in endocervical cells’, result code 8 according to the national health service cancer screening programme (NHSCSP), was excluded from the study.

Results:  A total of 200 women were identified using the hospitals’ pathology computer systems. Invasive carcinoma was found in 48 women (24%): 28 endocervical adenocarcinomas, eight squamous cell carcinomas (SCC), ten endometrial and two ovarian adenocarcinomas. Pre‐invasive neoplasia was found in 115 (57.5%), including 14 cervical glandular intraepithelial neoplasia (CGIN), 31 cervical intraepithelial neoplasia (CIN) grade 2/3 and 70 concomitant CGIN and CIN2/3. CIN1/HPV was found in 25, simple endometrial hyperplasia in three and no histological abnormality in three. Thirty‐four (70.8%) of 48 invasive carcinomas (of which 23 were endocervical adenocarcinomas) were in asymptomatic women investigated for abnormal cytology. Fourteen of 34 (41.4%) of those with ?glandular neoplasia thought to be endometrial were CGIN or CIN2/3. Colposcopic appearances were normal in 47.6% of women with pure cervical glandular neoplasia (adenocarcinoma or CGIN) compared with 12.8% with squamous cell lesions (CIN2/3 or SCC): P = 0.0001. Thus, colposcopy was more sensitive for detecting squamous cell abnormalities than their glandular counterparts. Although cervical adenocarcinomas are less amenable to prevention by screening than cervical SCC, in our study cervical cytology predominantly detected these abnormalities at their early asymptomatic stages.

Conclusion:  At least CIN2 was found in 81.5% in women referred with cervical cytology reporting ?glandular neoplasia. A thorough evaluation of the whole genital tract is needed if colposcopy is negative.
Pattern of adrenal morphology and function in patients with acromegaly
Authors: Pappa Theodora , Papanastasiou Labrini , Koutmos Spiros , Tsiavos Vaios , Roussaki Peggy , Zilos Athanasios , Ragkou Despina , Kaltsas Gregory , Piaditis George
Published: July 2011

Eur J Clin Invest 2012; 42 (3): 275–281

Background  Acromegaly is well known to induce hypertrophic and hyperplastic changes in various organs and is commonly accompanied by arterial hypertension. In our study, we assess the adrenal morphology and function in a series of patients with acromegaly and possible associations with the activity of the disease and arterial hypertension.

Materials and methods  Sixty patients with acromegaly, admitted to two endocrinology departments in the time period 2005–2010, were studied prospectively. Basal IGF‐1 and growth hormone levels after oral glucose tolerance test were used to assess the disease activity. All subjects underwent adrenal CT scan, basal adrenal hormonal investigation and evaluation with 24‐h urinary free cortisol and cortisol levels following low‐dose dexamethasone suppression test. In 33 acromegalics, the ‘modified’ saline infusion test (MSI), i.e. saline infusion after dexamethasone administration, was performed to identify autonomous aldosterone (ALD) secretion.

Results  Abnormal adrenal morphology was present in 48% of our patients, and a significant association was found between the presence of arterial hypertension and adrenal morphology. Among patients with adrenal morphological changes, 55% exhibited no adrenal secretory hyperactivity, 34% autonomous cortisol, 7% ALD and 4% combined autonomous cortisol and ALD secretion, when applying recently proposed modified cut‐off levels compared to widely used criteria. An increased prevalence of autonomous ALD secretion was shown among the subgroup of patients with acromegaly tested with MSI.

Conclusions  This study provides evidence of an increased prevalence of anatomic and functional adrenal alterations in patients with acromegaly; further studies will clarify the importance of evaluating these subjects with baseline hormonal investigation along with dynamic testing and modified cut‐offs.
A new HLA‐C allele, C*08:43, identified during a UCLA Immunogenetics Centre cell exchange
Authors: Cao K. , Street J. , Johnson J. , Wang Q. , Lau M. , Darke C.
Published: July 2011

HLA‐C*08:43 differs from HLA‐C*08:02:01 by one nucleotide (A>G) at position 584 resulting in an amino acid change of 171 tyrosine to 171 cysteine.
Disparity of innate immunity–related gene effects on asthma and allergy on Karelia
Authors: Zhang Guicheng , Candelaria Pierre , Mäkelä J. Mika , Khoo Siew‐Kim , Hayden M. Catherine , von Hertzen Leena , Laatikainen Tiina , Vartiainen Erkki , Goldblatt Jack , Haahtela Tari , LeSouëf N. Peter
Published: July 2011

To cite this article: Zhang G, Candelaria P, Mäkelä JM, Khoo S‐K, Hayden MC, von Hertzen L, Laatikainen T, Vartiainen E, Goldblatt J, Haahtela T, LeSouëf NP. Disparity of innate immunity–related gene effects on asthma and allergy on Karelia. Pediatr Allergy Immunol 2011; 22: 621–630.

Background:  We investigated the interactive effects of 11 innate immunity–related genes (IL10, IL12b, IL8, TLR2, TLR4, CD14, IFNGR, CC16, IFNg, CMA1, and TGFB) and four IgE response genes (IL4, IL13, IL4RA, and STAT6) with ‘Western’ or ‘Eastern’ environments/lifestyles on asthma and allergy in Karelian children.

Methods:  Karelian children (412 Finnish and 446 Russian) were recruited and assessed for a range of allergic conditions, with 24 single‐nucleotide polymorphisms genotyped in 15 genes.

Results:  The genotype–phenotype relationships differed in Finnish and Russian Karelian children. The interaction between polymorphisms and the variable representing ‘Western’ and ‘Eastern’ environments/ lifestyles was significant for IL10‐1082 (p = 0.0083) on current rhinitis, IL12b 6408 on current conjunctivitis (p = 0.016) and atopy (p = 0.034), IL8 781 on atopic eczema (p = 0.0096), CD14 ‐550 on current rhinitis (p = 0.022), IFNgR1 ‐56 on atopic eczema(p = 0.038), and STAT6 2964 on current itchy rash (p = 0.037) and total serum IgE (p = 0.042). In addition, the G allele of IL13 130 was associated with a lower level of total serum IgE in Finnish (p = 0.003) and Russian (p = 0.01) children and overall (pooling the two populations together, p = 0.00006). After adjusting for multiple tests, the association between IL13 130 and IgE and the interactive effects of IL10‐1082 on current rhinitis and IL8 781 on atopic eczema were significant by controlling a false‐positive rate of 0.05 and 0.10, respectively.

Conclusions:  Living in an Eastern vs. Western environment was associated with a different genetic profile associated with asthma and allergy in the Karelian populations.
Limited agreement between current and long‐term asthma control in children: the PACMAN cohort study
Authors: Koster Ellen S. , Raaijmakers Jan A. M. , Vijverberg Susanne J. H. , Koenderman Leo , Postma Dirkje S. , Koppelman Gerard H. , van der Ent Cornelis K. , Maitland‐van der Zee Anke‐Hilse
Published: July 2011

To cite this article: Koster ES, Raaijmakers JAM, Vijverberg SJH, Koenderman L, Postma DS, Koppelman GH, van der Ent CK, Maitland‐van der Zee A‐H. Limited agreement between current and long‐term asthma control in children: the PACMAN cohort study. Pediatr Allergy Immunol 2011: 22: 776–783

Background:  Several studies have shown that predictors of asthma treatment outcomes differ depending on the definition of the outcome chosen. This provides evidence that different outcomes studied may reflect distinct aspects of asthma control. To assess predictors of asthma control, we need firm outcome phenotypes. The aim of this study was to investigate the association between measurements of current and long‐term asthma control.

Methods:  We included 527 children using inhaled corticosteroids participating in the Pharmacogenetics of Asthma medication in Children: Medication with ANti‐inflammatory effects cohort. Current asthma control (previous week) was defined using the Asthma Control Questionnaire. Long‐term asthma control was based on Global Initiative for Asthma guidelines. Not well‐controlled asthma in a season was defined as ≥3 of the following items present in a season: (i) day‐time or (ii) night‐time symptoms, (iii) limitations in activities, and (iv) rescue medication use. Asthma control during (i) the previous season and (ii) the year preceding the pharmacy visit was used as long‐term asthma control definitions. Current and long‐term asthma control were compared to investigate agreement.

Results:  Long‐term uncontrolled asthma rates were highest in autumn and winter (50%) and lowest in summer (32%) (p < 0.05). Overall agreement between current and long‐term asthma control was limited (66% for previous season and 68% for previous year).

Conclusion:  Congruence between current and long‐term asthma control was limited. Furthermore, we showed significant seasonal differences. It is therefore important to calculate asthma control over a longer period of time, instead of using current asthma control as indicator.
Make‐up of the epinephrine autoinjector: the effect on its use by untrained users
Authors: Bakirtas Arzu , Arga Mustafa , Catal Ferhat , Derinoz Oksan , Demirsoy Mehmet S. , Turktas Ipek
Published: July 2011

To cite this article: Bakirtas A, Arga M, Catal F, Derinoz O, Demirsoy MS, Turktas I. Make‐up of the epinephrine autoinjector: the effect on its use by untrained users. Pediatric Allergy Immunology 2011; 22: 729–733.

Background:  Part of the problems related to proper use of the epinephrine autoinjector may be related to the design of the autoinjector itself.

Aim:  We investigated whether minor modifications in the design of the currently available epinephrine autoinjector ease its use and abrogate common use errors.

Methods:  All interns other than those who had previously worked in allergy department in a medical school were invited to the study. Two identical epinephrine autoinjector trainers (Epipen trainer®) were used, one of which was modified by changing the gray safety cap to red and placing a yellow arrow pointing to the black injection tip. A written and visual instruction sheet for each trainer was provided. Participants were asked to demonstrate the use of the Epipen trainer either with the original or with the modified one. They were scored and timed for their demonstration.

Results:  Out of the 224 interns who were invited to participate, one hundred and sixty‐four interns (73.2%) participated in the study. The number of participants correctly demonstrating the use of epinephrine autoinjectors was 22.6% and 65% in unmodified and modified trainer groups, respectively (p < 0.001). The mean time to administer trainers was 26.78 ± 10.6 and 15.88 ± 2.55 s; total median scores were 3.08 ± 1.48 and 4.47 ± 0.84 in unmodified and modified groups, respectively (p < 0.001 for both). Significantly fewer participants had presumptive unintentional injection injury while using modified (5%) compared with unmodified trainer (45.2%) (p < 0.001).

Conclusion:  Few and simple modifications in the design of epinephrine autoinjector were found effective in increasing its correct use and decreasing common use errors by untrained users. (Clinical trials identifier: NCT01217138).
Tyrosinemia type 1 in Spain: Mutational analysis, treatment and long‐term outcome
Authors: Couce Maria Luz , Dalmau Jaime , del Toro Mireia , Pintos‐Morell Guillem , Aldámiz‐Echevarría Luís ,   Spanish Working Group on Tyrosinemia type1
Published: July 2011

Background:  Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long‐term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype–phenotype correlation.

Methods:  A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1.

Results:  The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α‐fetoprotein and coagulopathy. The most common mutation was IVS6‐1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma.

Conclusions:  Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6‐1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6‐1(G > T) mutation was observed.
‘I love you’. How to understand love in couple therapy? Exploring love in context
Authors: Migerode Lieven , Hooghe An
Published: July 2011

Acknowledging the place of love in couple therapy requires therapists to reflect upon what love means to them. We propose that love defines the couple relationship and in turn the relationship defines love. In this article we explore and focus on our conceptualization of love and its influence on couple therapy. Exploring love in the context of the phrase ‘I love you’ leads us to consider built‐in contradictions. These contradictions can be contextualized and understood in a relational dialectic framework. Implications for therapy are explored and briefly illustrated in a case vignette.
Ten Years of Monitoring Illicit Drug Use in Prison Populations in Europe: Issues and Challenges
Authors: CARPENTIER CHLOÉ , ROYUELA LUIS , NOOR ANDRÉ , HEDRICH DAGMAR
Published: July 2011

Abstract: The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been collecting aggregated data on illicit drug use among European prison populations for over a decade. Additional studies were identified in a literature search. Together, these sources yielded 53 studies reporting data during the period 2000 to 2008. Analysis of these studies reveals that the available data are scarce and patchy, with large variations in methodology. This diversity hampers comparison, and may, in part, account for the wide range of prevalence estimates for drug use and drug injecting, both prior to imprisonment and while in prison. This article concludes that a common instrument to measure drug use and its consequences in European prison populations is needed.
Molecular Docking, 3D‐QSAR Studies, and In Silico ADME Prediction of p‐Aminosalicylic Acid Derivatives as Neuraminidase Inhibitors
Authors: Zhang Jie , Shan Yuanyuan , Pan Xiaoyan , Wang Chen , Xu Wenfang , He Langchong
Published: July 2011

Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug design and discovery. To develop novel potent neuraminidase inhibitors (NAI), Surflex‐Dock was employed to dock 40 hydrophobic p‐aminosalicylic acid derivatives into the active site of NA. The 3D‐quantitative structure–activity relationship studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 40 molecules. Both CoMFA (q2 = 0.628, r2 = 0.697) and CoMSIA (q2 = 0.746, r2 = 0.816) gave reasonable results. A preliminary pharmacokinetic profile of these NAI was also performed on the basis of Volsurf predictions. The results obtained from this study will be useful in the design of novel potent NAI.
A Critical Subset Model Provides a Conceptual Basis for the High Antiviral Activity of Major HIV Drugs
Authors: Shen Lin , Rabi S. Alireza , Sedaghat Ahmad R. , Shan Liang , Lai Jun , Xing Sifei , Siliciano Robert F.
Published: July 2011

Disruption of the cooperative action of multiple copies of a drug target explains the high antiviral activity of the most active HIV drugs.
SIMPLICITY OF EXTREMAL EIGENVALUES OF THE KLEIN–GORDON EQUATION
Authors: KOPPEN MARIO , TRETTER CHRISTIANE , WINKLMEIER MONIKA
Published: July 2011

We consider the spectral problem associated with the Klein–Gordon equation for unbounded electric potentials such that the spectrum is contained in two disjoint real intervals related to positive and negative energies, respectively. If the two inner boundary points are eigenvalues, we show that these extremal eigenvalues are simple and possess strictly positive eigenfunctions. Examples of electric potentials satisfying these assumptions are given.
MONOPHONIC DISTANCE IN GRAPHS
Authors: SANTHAKUMARAN A. P. , TITUS P.
Published: July 2011

For any two vertices u and v in a connected graph G, a u – v path is a monophonic path if it contains no chords, and the monophonic distance dm(u, v) from u to v is defined as the length of a longest u – v monophonic path in G. A u – v monophonic path of length dm(u, v) is called a u – v monophonic. The monophonic eccentricity em(v) of a vertex v in G is the maximum monophonic distance from v to a vertex of G. The monophonic radius rad m G of G is the minimum monophonic eccentricity among the vertices of G, while the monophonic diameter diam m G of G is the maximum monophonic eccentricity among the vertices of G. It is shown that rad m G ≤ diam m G for every connected graph G and that every pair a, b of positive integers with a ≤ b is realizable as the monophonic radius and monophonic diameter of some connected graph. Also, for any three positive integers a, b and c with 3 ≤ a ≤ b ≤ c, there is a connected graph G such that rad G = a, rad m G = b and rad DG = c; and for any three positive integers a, b and c with 5 ≤ a ≤ b ≤ c, there is a connected graph G such that diam G = a, diam m G = b and diam D G = c, where rad G, diam G, rad DG and diam D G denote the radius, diameter, detour radius and detour diameter, respectively. The monophonic center of G is the subgraph induced by the vertices of G having monophonic eccentricity rad m G and it is shown that every graph is the monophonic center of some connected graph and also that the monophonic center Cm(G) of every connected graph G is a subgraph of some block of G.
Homocysteine suppresses lipolysis in adipocytes by activating the AMPK pathway
Authors: Wang Zhigang , Pini Maria , Yao Tong , Zhou Zhanxiang , Sun Changhao , Fantuzzi Giamila , Song Zhenyuan
Published: July 2011

Hyperhomocysteinemia (HHcy) is an independent risk factor for coronary artery disease. Emerging evidence suggests that HHcy is also associated with adipocyte tissue dysfunction. One of the principal functions of adipose tissue is to provide energy substrate via lipolysis. In the present study, we investigated the effects of homocysteine (Hcy) on lipolysis in adipocytes. We found that Hcy inhibited release of glycerol and fatty acids, two typical indicators of the lipolytic response, in primary adipocytes and fully differentiated 3T3-L1 adipocytes in a dose-dependent manner under both basal and isoproterenol-stimulated conditions. In differentiated 3T3-L1 adipocytes, decreased glycerol and free fatty acid (FFA) release was associated with elevation of intracellular TG content. Further studies showed that Hcy-mediated antilipolytic responses were independent of the cyclic AMP-PKA and MEK-ERK1/2 pathways. However, Hcy increased phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream enzyme acetyl-CoA carboxylase. Compound C, an AMPK inhibitor, abolished Hcy-induced reduction of glycerol and FFA release under both basal and isoproterenol-stimulated conditions. Furthermore, AMPKα1 siRNA reversed Hcy-inhibited glycerol release. Supplementation of exogenous Hcy in the diet for 2 wk lowered circulating glycerol and FFA levels. Moreover, Hcy supplementation was associated with elevated leptin levels and reduced adiponectin levels in plasma. These results show that Hcy inhibits lipolysis through a pathway that involves AMPK activation.
Context dependence of receptive field remapping in superior colliculus
Authors: Churan Jan , Guitton Daniel , Pack Christopher C.
Published: July 2011

Our perception of the positions of objects in our surroundings is surprisingly unaffected by movements of the eyes, head, and body. This suggests that the brain has a mechanism for maintaining perceptual stability, based either on the spatial relationships among visible objects or internal copies of its own motor commands. Strong evidence for the latter mechanism comes from the remapping of visual receptive fields that occurs around the time of a saccade. Remapping occurs when a single neuron responds to visual stimuli placed presaccadically in the spatial location that will be occupied by its receptive field after the completion of a saccade. Although evidence for remapping has been found in many brain areas, relatively little is known about how it interacts with sensory context. This interaction is important for understanding perceptual stability more generally, as the brain may rely on extraretinal signals or visual signals to different degrees in different contexts. Here, we have studied the interaction between visual stimulation and remapping by recording from single neurons in the superior colliculus of the macaque monkey, using several different visual stimulus conditions. We find that remapping responses are highly sensitive to low-level visual signals, with the overall luminance of the visual background exerting a particularly powerful influence. Specifically, although remapping was fairly common in complete darkness, such responses were usually decreased or abolished in the presence of modest background illumination. Thus the brain might make use of a strategy that emphasizes visual landmarks over extraretinal signals whenever the former are available.
Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography
Authors: van der Veldt Astrid A.M. , Lubberink Mark , Greuter Henri N. , Comans Emile F.I. , Herder Gerarda J.M. , Yaqub Maqsood , Schuit Robert C. , van Lingen Arthur , Rizvi S. Nafees , Mooijer Martien P.J. , Rijnders Anneloes Y. , Windhorst Albert D. , Smit Egbert F. , Hendrikse N. Harry , Lammertsma Adriaan A.
Published: July 2011

Purpose: Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [11C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [11C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration.

Experimental Design: Thirty-four lung cancer patients underwent dynamic PET–computed tomography (CT) scans using [11C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [11C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated.

Results: Reproducible quantification of [11C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm3) were identified, having a variable net influx rate of [11C]docetaxel (range, 0.0023–0.0229 mL·cm−3·min−1). [11C]docetaxel uptake was highly related to tumor perfusion (Spearman's ρ = 0.815;P < 0.001), but not to tumor size (Spearman's ρ = −0.140; P = 0.446). Patients pretreated with dexamethasone showed lower [11C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [11C]docetaxel uptake was related with improved tumor response.

Conclusions: Quantification of [11C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [11C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [11C]docetaxel uptake and the effects of comedication on [11C]docetaxel kinetics in tumors. Clin Cancer Res; 17(14); 4814–24. ©2011 AACR.
Spectrum of Cellular Responses to Pyriplatin, a Monofunctional Cationic Antineoplastic Platinum(II) Compound, in Human Cancer Cells
Authors: Lovejoy Katherine S. , Serova Maria , Bieche Ivan , Emami Shahin , D'Incalci Maurizio , Broggini Massimo , Erba Eugenio , Gespach Christian , Cvitkovic Esteban , Faivre Sandrine , Raymond Eric , Lippard Stephen J.
Published: July 2011

Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum–DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC50 = 171–443 μmol/L), with maximum cytotoxicity in HOP-62 non–small cell lung cancer cells after 72 hours (IC50 = 24 μmol/L). Pyriplatin caused a G2-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin–DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use. Mol Cancer Ther; 10(9); 1709–19. ©2011 AACR.
Risk Stratification and Prognosis of Human Immunodeficiency Virus–Infected Patients With Known or Suspected Coronary Artery Disease Referred for Stress Echocardiography
Authors: Wever Pinzon Omar , Silva Enciso Jorge , Romero Jorge , Makani Harikrishna , Fefer Jose , Gandhi Vani , Bangalore Sripal , Chaudhry Farooq A.
Published: July 2011

Background—

Patients with human immunodeficiency virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV-infected patients with known or suspected CAD.

Methods and Results—

We evaluated 311 patients (age, 52±9 years; 74% men; left ventricular ejection fraction, 54±12%) with history of HIV, undergoing SE (56% dobutamine). Left ventricular wall motion was evaluated on a 16-segment model, 5-point scale. An abnormal SE was defined by a fixed (infarction), biphasic, or new (ischemia) wall motion abnormality on stress. Follow-up for cardiac death and myocardial infarction was obtained. Seventy-nine (26%) patients had an abnormal SE. After 2.9±1.9 years, 17 confirmed myocardial infarction and 14 cardiac deaths occurred. SE risk-stratified patients into normal versus abnormal subgroups (event rate, 0.6% per year versus 11.8% per year;
P
<0.0001). Both abnormal SE (hazard ratio, 28.2; 95% confidence interval, 6.2 to 128.0;
P
<0.0001) and the presence of any ischemia on SE (hazard ratio, 3.4; 95% confidence interval, 1.3 to 8.6;
P
=0.009) were independent predictors of cardiac events. On a forward conditional Cox proportional hazards regression model, SE provided incremental prognostic value over clinical, stress ECG, and resting echocardiographic variables (global χ
2
increased from 17.8 to 24.5 to 65 to 109,
P
<0.05 across all groups).

Conclusions—

SE can effectively risk-stratify and prognosticate patients with HIV. The presence of ischemia and scar during SE provides independent and incremental prognostic value over traditional variables. A normal SE response portends a benign prognosis even in this high-risk subset.
Three-Apogee 16-h Highly Elliptical Orbit as Optimal Choice for Continuous Meteorological Imaging of Polar Regions
Authors: Trishchenko Alexander P. , Garand Louis , Trichtchenko Larisa D.
Published: July 2011

A highly elliptical orbit (HEO) with a 16-h period is proposed for continuous meteorological imaging of polar regions from a two-satellite constellation. This orbit is characterized by three apogees (TAP) separated by 120°. The two satellites are 8 h apart, with repeatable ground track in the course of 2 days. Advantages are highlighted in comparison to the Molniya 12-h orbit described in detail in a previous study (Trishchenko and Garand). Orbital parameters (period, eccentricity, and inclination) are obtained as a result of an optimization process. The principles of orbit optimization are based on the following four key requirements: spatial resolution (apogee height), the altitude of crossing the trapped proton region at the equator (minimization of radiation doze caused by trapped protons), imaging time over the polar regions, and the stability of the orbit, which is mostly defined by the rotation of perigee. The interplay between these requirements points to a 16-h period with an eccentricity of 0.55 as the optimum solution. The practical range of orbit inclinations that could be maintained during the spacecraft lifetime can vary from a critical value of 63.435° to 70° (subject to the amount of propellant available for orbital maneuvers). In comparison to Molniya, this type of orbit reduces the radiation exposure to high-energy protons by factor of 103–104. On the other hand, the main advantage of 16 h versus longer orbital periods up to 24 h is better spatial resolution as a result of a lower apogee height. A two-satellite TAP constellation with an orbital inclination of 66° provides 100% temporal coverage above 60°N, >95% above 55°N, >85% above 50°N, and >75% above 45°N.
Provision of Balanced Nutrition Protects Against Hypoglycemia in the Critically Ill Surgical Patient
Authors: Kauffmann Rondi M. , Hayes Rachel M. , Jenkins Judith M. , Norris Patrick R. , Diaz Jose J. , May Addison K. , Collier Bryan R.
Published: July 2011

Background: Intensive insulin therapy lowers blood glucose and improves outcomes but increases the risk of hypoglycemia. Typically, insulin protocols require a dextrose solution to prevent hypoglycemia. The authors hypothesized that the provision of balanced nutrition (enteral nutrition [EN] or parenteral nutrition [PN]) would be more protective against hypoglycemia (≤50 mg/dL) than carbohydrate alone. Methods: A retrospective analysis was performed of patients treated with intensive insulin therapy and surviving ≥24 hours. The computer‐based insulin protocol requires infusion of D10W at 30 mL/h if EN or PN is not provided. Nutrition provision was assessed in 2‐hour increments, comparing periods of blood glucose control with and without balanced nutrition. The risk of hypoglycemia for each blood glucose measurement was estimated by multivariable regression. Results: In total, 66,592 glucose measurements were collected on 1392 patients. Hypoglycemic events occurred in 5.8/1000 glucose tests after 2 hours without balanced nutrition compared to 2.2/1000 tests when balanced nutrition was given in the preceding 2 hours. In multivariable regression models, balanced nutrition was the strongest protective factor against hypoglycemia. Patients who did not receive balanced nutrition in the preceding 2 hours had a 3 times increase in the odds of a hypoglycemic event at their next glucose check (odds ratio = 3.6, P < .001). Providing carbohydrate alone was not protective. Conclusions: Balanced nutrition is associated with reduced risk of hypoglycemia. These results suggest that balanced nutrition should be given when insulin therapy is initiated. Future studies should evaluate the efficacy of EN vs PN in preventing hypoglycemia.
Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G > A mitochondrial DNA mutation: a case report
Authors: Ronchi Dario , Cosi Alessandra , Tonduti Davide , Orcesi Simona , Bordoni Andreina , Fortunato Francesco , Rizzuti Mafalda , Sciacco Monica , Collotta Martina , Cagdas Sophie , Capovilla Giuseppe , Moggio Maurizio , Berardinelli Angela , Veggiotti Pierangelo , Comi Giacomo P
Published: July 2011

Background

Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors.

Case presentation

Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C > G and the already known m.14459G > A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G > A was heteroplasmic in the mother's blood-derived DNA.

Conclusions

The m.14459G > A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G > A-mutated patients does not explain this large clinical heterogeneity.
Inhaled nitric oxide for the adjunctive therapy of severe malaria: Protocol for a randomized controlled trial
Authors: Hawkes Michael , Opoka Robert O , Namasopo Sophie , Miller Christopher , Thorpe Kevin E , Lavery James V , Conroy Andrea L , Liles W Conrad , John Chandy C , Kain Kevin C
Published: July 2011

Background

Severe malaria remains a major cause of global morbidity and mortality. Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high. Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality. Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator. Nitric oxide (NO) is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes. Low-flow inhaled nitric oxide (iNO) gas is a US FDA-approved treatment for hypoxic respiratory failure in neonates.

Methods/Design

This prospective, parallel arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous inhaled nitric oxide at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1-10 years of age with severe malaria. The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analysed using a mixed-effects linear model. Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.

Discussion

Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.

Trial Registration

ClinicalTrials.gov Identifier: NCT01255215
Co-hydrolysis of hydrothermal and dilute acid pretreated populus slurries to support development of a high-throughput pretreatment system
Authors: Studer Michael H , Brethauer Simone , DeMartini Jaclyn D , McKenzie Heather L , Wyman Charles E
Published: July 2011

Background

The BioEnergy Science Center (BESC) developed a high-throughput screening method to rapidly identify low-recalcitrance biomass variants. Because the customary separation and analysis of liquid and solids between pretreatment and enzymatic hydrolysis used in conventional analyses is slow, labor-intensive and very difficult to automate, a streamlined approach we term 'co-hydrolysis' was developed. In this method, the solids and liquid in the pretreated biomass slurry are not separated, but instead hydrolysis is performed by adding enzymes to the whole pretreated slurry. The effects of pretreatment method, severity and solids loading on co-hydrolysis performance were investigated.

Results

For hydrothermal pretreatment at solids concentrations of 0.5 to 2%, high enzyme protein loadings of about 100 mg/g of substrate (glucan plus xylan) in the original poplar wood achieved glucose and xylose yields for co-hydrolysis that were comparable with those for washed solids. In addition, although poplar wood sugar yields from co-hydrolysis at 2% solids concentrations fell short of those from hydrolysis of washed solids after dilute sulfuric acid pretreatment even at high enzyme loadings, pretreatment at 0.5% solids concentrations resulted in similar yields for all but the lowest enzyme loading.

Conclusions

Overall, the influence of severity on susceptibility of pretreated substrates to enzymatic hydrolysis was clearly discernable, showing co-hydrolysis to be a viable approach for identifying plant-pretreatment-enzyme combinations with substantial advantages for sugar production.
MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice
Authors: Pal-Ghosh Sonali , Blanco Tomas , Tadvalkar Gauri , Pajoohesh-Ganji Ahdeah , Parthasarathy Arpitha , Zieske James D. , Stepp Mary Ann
Published: July 2011

Integrin α6β4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo: (1) MMP9 levels are elevated and β4 integrin is partially cleaved in epithelial cell extracts derived from debridement wounded corneas; (2) the β4 ectodomain is missing from sites where erosions develop; and (3) β4 cleavage can be reduced by inhibiting MMP activity. Although β4, α3 and β1 integrins were all cleaved by several MMPs, only MMP9 was elevated in cell extracts derived from corneas with erosions. Coimmunoprecipitation studies showed that β4 integrin associates with MMP9, and protein clustering during immunoprecipitation induced proteolytic cleavage of the β4 integrin extracellular domain, generating a 100 kDa β4 integrin cytoplasmic domain fragment. Confocal imaging with three-dimensional reconstruction showed that MMP9 localizes at erosion sites in vivo where the ectodomain of β4 integrin is reduced or absent. MMP activation experiments using cultured corneal and epidermal keratinocytes showed reduced levels of α6β4 and β1 integrins within 20 minutes of phorbol ester treatment. This report is the first to show that β4 integrin associates with MMP9 and that its ectodomain is a target for cleavage by MMP9 in vivo under pathological conditions.
Microtubule remodelling is required for the front–rear polarity switch during contact inhibition of locomotion
Authors: Kadir Shereen , Astin Jonathan W. , Tahtamouni Lubna , Martin Paul , Nobes Catherine D.
Published: July 2011

When migrating mesenchymal cells collide, they exhibit a ‘contact inhibition of locomotion’ response that results in reversal of their front–rear polarity by extension of a new leading edge, which enables their migration away from the opposing contacted cell. The critical cytoskeletal rearrangements underpinning these mutual repulsion events are currently unknown. We found that during fibroblast cell–cell collisions, microtubules at the region of contact increase their frequency of catastrophe, their rates of shrinkage and growth, and concomitantly, a new microtubule array is established at a new leading edge. We show that Rho and ROCK activity is necessary for this repulsion response, and we observed increased microtubule stabilisation as a consequence of ROCK inhibition. Importantly, partial destabilisation of microtubules, by co-treatment with a low dose of nocodazole, restored microtubule dynamics to that of untreated cells and rescued contact inhibition of locomotion in ROCK-inhibited cells. Although there was an increase in microtubule growth or shrinkage rates in Y27632 cell–cell collisions, these failed to reach the same level of dynamicity compared with untreated collisions. Our data suggest that microtubule dynamics at contact sites must increase beyond a threshold for a cell to switch its front–rear polarity, and that microtubule stabilisation can lead to a failure of contact inhibition of locomotion.
Not all songbirds calibrate their magnetic compass from twilight cues: a telemetry study
Authors: Chernetsov Nikita , Kishkinev Dmitry , Kosarev Vladislav , Bolshakov Casimir V.
Published: July 2011

Migratory birds are able to use the sun and associated polarised light patterns, stellar cues and the geomagnetic field for orientation. No general agreement has been reached regarding the hierarchy of orientation cues. Recent data from naturally migrating North American Catharus thrushes suggests that they calibrate geomagnetic information daily from twilight cues. Similar results have been shown in caged birds in a few studies but not confirmed in others. We report that free-flying European migrants, song thrushes Turdus philomelos, released after pre-exposure to a horizontally rotated magnetic field, do not recalibrate their magnetic compass from solar cues, but rather show a simple domination of either the magnetic or the stellar compass. We suggest that different songbird species possess different hierarchies of orientation cues, depending on the geographic and ecological challenges met by the migrants.
Unraveling regulation and new components of human P-bodies through a protein interaction framework and experimental validation
Authors: Zheng Dinghai , Chen Chyi-Ying A. , Shyu Ann-Bin
Published: July 2011

The cellular factors involved in mRNA degradation and translation repression can aggregate into cytoplasmic domains known as GW bodies or mRNA processing bodies (P-bodies). However, current understanding of P-bodies, especially the regulatory aspect, remains relatively fragmentary. To provide a framework for studying the mechanisms and regulation of P-body formation, maintenance, and disassembly, we compiled a list of P-body proteins found in various species and further grouped both reported and predicted human P-body proteins according to their functions. By analyzing protein–protein interactions of human P-body components, we found that many P-body proteins form complex interaction networks with each other and with other cellular proteins that are not recognized as P-body components. The observation suggests that these other cellular proteins may play important roles in regulating P-body dynamics and functions. We further used siRNA-mediated gene knockdown and immunofluorescence microscopy to demonstrate the validity of our in silico analyses. Our combined approach identifies new P-body components and suggests that protein ubiquitination and protein phosphorylation involving 14-3-3 proteins may play critical roles for post-translational modifications of P-body components in regulating P-body dynamics. Our analyses provide not only a global view of human P-body components and their physical interactions but also a wealth of hypotheses to help guide future research on the regulation and function of human P-bodies.
Massive Changes in Genome Architecture Accompany the Transition to Self-Fertility in the Filamentous FungusNeurospora tetrasperma
Authors: Ellison Christopher E , Stajich Jason E , Jacobson David J , Natvig Donald O , Lapidus Alla , Foster Brian , Aerts Andrea , Riley Robert , Lindquist Erika A , Grigoriev Igor V , Taylor John W
Published: July 2011

A large region of suppressed recombination surrounds the sex-determining locus of the self-fertile fungus Neurospora tetrasperma. This region encompasses nearly one-fifth of the N. tetrasperma genome and suppression of recombination is necessary for self-fertility. The similarity of the N. tetrasperma mating chromosome to plant and animal sex chromosomes and its recent origin (<5 MYA), combined with a long history of genetic and cytological research, make this fungus an ideal model for studying the evolutionary consequences of suppressed recombination. Here we compare genome sequences from two N. tetrasperma strains of opposite mating type to determine whether structural rearrangements are associated with the nonrecombining region and to examine the effect of suppressed recombination for the evolution of the genes within it. We find a series of three inversions encompassing the majority of the region of suppressed recombination and provide evidence for two different types of rearrangement mechanisms: the recently proposed mechanism of inversion via staggered single-strand breaks as well as ectopic recombination between transposable elements. In addition, we show that the N. tetrasperma mat a mating-type region appears to be accumulating deleterious substitutions at a faster rate than the other mating type (mat A) and thus may be in the early stages of degeneration.