bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regression of aortic valve stenosis by ApoA‐I mimetic peptide infusions in rabbits
Authors: Busseuil D , Shi Y , Mecteau M , Brand G , Kernaleguen A‐E , Thorin E , Latour J‐G , Rhéaume E , Tardif J‐C 
Published: April 2008

Background and purpose:Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A‐I (ApoA‐I) mimetic peptide infusions could induce regression of AVS.Experimental approach:Fifteen New Zealand White male rabbits received a cholesterol‐enriched diet and vitamin D2 until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol‐lowering therapy and animals were allocated randomly to receive saline (control group, n=8) or an ApoA‐I mimetic peptide (treated group, n=7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed.Key results:Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P=0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P=0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P=0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r=0.87, P=0.004) between calcification area and aortic valve thickness.Conclusions and implications:Infusions of ApoA‐I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high‐density lipoprotein (HDL)‐based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease.British Journal of Pharmacology (2008) 154, 765–773; doi:10.1038/bjp.2008.122; published online 14 April 2008
A neuropeptide‐centric view of psychostimulant addiction
Authors: Boutrel B 
Published: April 2008

Drugs of abuse all share common properties classically observed in human beings and laboratory animals. They enhance neural firing and dopamine tone within the nucleus accumbens and produce progressively greater drug‐induced motor responses defined as behavioural sensitization. They produce conditioned place preference, a behavioural model of incentive motivation, which highlights the role of environmental cues in drug addiction. They increase brain reward function as seen by a lowering of intracranial self‐stimulation thresholds. And last but not least, they are self‐administered, and sometimes even abused, and can trigger reinstatement of drug‐seeking behaviour in animals extinguished from drug self‐administration. It has long been considered that the reinforcing properties of virtually all drugs of abuse, more specifically psychostimulants, are primarily dependent on activation of the mesolimbic dopamine system. However, recent evidence raises the importance of dopamine‐independent mechanisms in reward‐related behaviours. The overwhelming body of evidence that indicates a critical role for the mesolimbic dopamine system in the reinforcing effect of psychostimulants should not mask the key contribution of other modulatory systems in the brain. This review summarizes the complex and subtle role of several neuropeptidergic systems in various aspects of addictive behaviours observed in laboratory animals exposed to psychostimulants. A special emphasis is given to the cannabinoid, opioid, nociceptin/orphanin FQ, corticotropin‐releasing factor and hypocretin/orexin systems. The relevance of these systems viewed as potential therapeutic targets for drug addiction is discussed in the light of their narrow pharmacological profile and their effectiveness in preventing drug addiction at doses usually not accompanied by severe side effects.British Journal of Pharmacology (2008) 154, 343–357; doi:10.1038/bjp.2008.133; published online 14 April 2008
Nitric oxide mediates NMDA-induced persistent inhibition of protein synthesis through dephosphorylation of eukaryotic initiation factor 4E-binding protein 1 and eukaryotic initiation factor 4G proteolysis
Authors: Petegnief Valérie , Font-Nieves Míriam , Martín M. Elena , Salinas Matilde , Planas Anna M. 
Published: April 2008

Cerebral ischaemia causes long-lasting protein synthesis inhibition that is believed to contribute to brain damage. Energy depletion promotes translation inhibition during ischaemia, and the phosphorylation of eIF (eukaryotic initiation factor) 2α is involved in the translation inhibition induced by early ischaemia/reperfusion. However, the molecular mechanisms underlying prolonged translation down-regulation remain elusive. NMDA (N-methyl-D-aspartate) excitotoxicity is also involved in ischaemic damage, as exposure to NMDA impairs translation and promotes the synthesis of NO (nitric oxide), which can also inhibit translation. In the present study, we investigated whether NO was involved in NMDA-induced protein synthesis inhibition in neurons and studied the underlying molecular mechanisms. NMDA and the NO donor DEA/NO (diethylamine–nitric oxide sodium complex) both inhibited protein synthesis and this effect persisted after a 30 min exposure. Treatments with NMDA or NO promoted calpain-dependent eIF4G cleavage and 4E-BP1 (eIF4E-binding protein 1) dephosphorylation and also abolished the formation of eIF4E–eIF4G complexes; however, they did not induce eIF2α phosphorylation. Although NOS (NO synthase) inhibitors did not prevent protein synthesis inhibition during 30 min of NMDA exposure, they did abrogate the persistent inhibition of translation observed after NMDA removal. NOS inhibitors also prevented NMDA-induced eIF4G degradation, 4E-BP1 dephosphorylation, decreased eIF4E–eIF4G-binding and cell death. Although the calpain inhibitor calpeptin blocked NMDA-induced eIF4G degradation, it did not prevent 4E-BP1 dephosphorylation, which precludes eIF4E availability, and thus translation inhibition was maintained. The present study suggests that eIF4G integrity and hyperphosphorylated 4E-BP1 are needed to ensure appropriate translation in neurons. In conclusion, our data show that NO mediates NMDA-induced persistent translation inhibition and suggest that deficient eIF4F activity contributes to this process.
Trp359 regulates flavin thermodynamics and coenzyme selectivity in Mycobacterium tuberculosis FprA
Authors: Neeli Rajasekhar , Sabri Muna , McLean Kirsty J. , Dunford Adrian J. , Scrutton Nigel S. , Leys David , Munro Andrew W. 
Published: April 2008

Mtb (Mycobacterium tuberculosis) FprA (flavoprotein reductase A) is an NAD(P)H-dependent FAD-binding reductase that is structurally related to mammalian adrenodoxin reductase, and which supports the catalytic function of Mtb cytochrome P450s. Trp359, proximal to the FAD, was investigated in light of its potential role in controlling coenzyme interactions, as observed for similarly located aromatic residues in diflavin reductases. Phylogenetic analysis indicated that a tryptophan residue corresponding to Trp359 is conserved across FprA-type enzymes and in adrenodoxin reductases. W359A/H mutants of Mtb FprA were generated, expressed and the proteins characterized to define the role of Trp359. W359A/H mutants exhibited perturbed UV-visible absorption/fluorescence properties. The FAD semiquinone formed in wild-type NADPH-reduced FprA was destabilized in the W359A/H mutants, which also had more positive FAD midpoint reduction potentials (−168/−181 mV respectively, versus the standard hydrogen electrode, compared with −230 mV for wild-type FprA). The W359A/H mutants had lower ferricyanide reductase kcat and NAD(P)H Km values, but this led to improvements in catalytic efficiency (kcat/Km) with NADH as reducing coenzyme (9.6/18.8 μM−1·min−1 respectively, compared with 5.7 μM−1·min−1 for wild-type FprA). Stopped-flow spectroscopy revealed NAD(P)H-dependent FAD reduction as rate-limiting in steady-state catalysis, and to be retarded in mutants (e.g. limiting rate constants for NADH-dependent FAD reduction were 25.4 s−1 for wild-type FprA and 4.8 s−1/13.4 s−1 for W359A/H mutants). Diminished mutant FAD content (particularly in W359H FprA) highlighted the importance of Trp359 for flavin stability. The results demonstrate that the conserved Trp359 is critical in regulating FprA FAD binding, thermodynamic properties, catalytic efficiency and coenzyme selectivity.
ArHsp21, a developmentally regulated small heat-shock protein synthesized in diapausing embryos of Artemia franciscana
Authors: Qiu Zhijun , MacRae Thomas H. 
Published: April 2008

Embryos of the crustacean, Artemia franciscana, undergo alternative developmental pathways, producing either larvae or encysted embryos (cysts). The cysts enter diapause, characterized by exceptionally high resistance to environmental stress, a condition thought to involve the sHSP (small heat-shock protein), p26. Subtractive hybridization has revealed another sHSP, termed ArHsp21, in diapause-destined Artemia embryos. ArHsp21 shares sequence similarity with p26 and sHSPs from other organisms, especially in the α-crystallin domain. ArHsp21 is the product of a single gene and its synthesis occurred exclusively in diapause-destined embryos. Specifically, ArHsp21 mRNA appeared 2 days post-fertilization, followed 1 day later by the protein, and then increased until embryo release at day 5. No ArHsp21 protein was detected in embryos developing directly into larvae, although there was a small amount of mRNA at 3 days post-fertilization. The protein was degraded during post-diapause development and had disappeared completely from second instar larvae. ArHsp21 formed large oligomers in encysted embryos and transformed bacteria. When purified from bacteria, ArHsp21 functioned as a molecular chaperone in vitro, preventing heat-induced aggregation of citrate synthase and reduction-driven denaturation of insulin. Sequence characteristics, synthesis patterns and functional properties demonstrate clearly that ArHsp21 is an sHSP able to chaperone other proteins and contribute to stress tolerance during diapause. As such, ArHsp21 would augment p26 chaperone activity and it may also possess novel activities that benefit Artemia embryos exposed to stress.
A critical role in structure-specific DNA binding for the acetylatable lysine residues in HMGB1
Authors: Assenberg René , Webb Michelle , Connolly Edward , Stott Katherine , Watson Matthew , Hobbs Josie , Thomas Jean O. 
Published: April 2008

The structure-specific DNA-binding protein HMGB1 (high-mobility group protein B1) which comprises two tandem HMG boxes (A and B) and an acidic C-terminal tail, is acetylated in vivo at Lys2 and Lys11 in the A box. Mutation to alanine of both residues in the isolated A domain, which has a strong preference for pre-bent DNA, abolishes binding to four-way junctions and 88 bp DNA minicircles. The same mutations in full-length HMGB1 also abolish its binding to four-way junctions, and binding to minicircles is substantially impaired. In contrast, when the acidic tail is absent (AB di-domain) there is little effect of the double mutation on four-way junction binding, although binding to minicircles is reduced ∼15-fold. Therefore it appears that in AB the B domain is able to substitute for the non-functional A domain, whereas in full-length HMGB1 the B domain is masked by the acidic tail. In no case does single substitution of Lys2 or Lys11 abolish DNA binding. The double mutation does not significantly perturb the structure of the A domain. We conclude that Lys2 and Lys11 are critical for binding of the isolated A domain and HMGB1 to distorted DNA substrates.
Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension
Authors: Rodrigo Ramón , Prat Hernán , Passalacqua Walter , Araya Julia , Bächler Jean P. 
Published: April 2008

Oxidative stress has been associated with mechanisms of EH (essential hypertension). The aim of the present study was to test the hypothesis that the antioxidant properties of vitamins C and E are associated with a decrease in BP (blood pressure) in patients with EH. A randomized double-blind placebo-controlled clinical trial was conducted in 110 men with grade 1 EH (35–60 years of age without obesity, dyslipidaemia and diabetes mellitus, non-smokers, not undergoing vigorous physical exercise, without the use of any medication and/or high consumption of fruit and vegetables). Participants were randomly assigned to receive either vitamins C+E [vitamin C (1 g/day) plus vitamin E (400 international units/day)] or placebo for 8 weeks. Measurements included 24 h ambulatory BP and blood analysis of oxidative-stress-related parameters in erythrocytes (GSH/GSSH ratio, antioxidant enzymes and malondialdehyde) and plasma [FRAP (ferric reducing ability of plasma)], and levels of 8-isoprostane, vitamins C and E were measured at baseline and after treatment. Following administration of vitamins C+E, patients with EH had significantly lower systolic BP, diastolic BP and mean arterial BP and higher erythrocyte and serum antioxidant capacity compared with either placebo-treated patients with EH or the patients with EH at baseline prior to treatment. BP correlated positively with plasma 8-isoprostane levels and negatively with plasma FRAP levels in the vitamins C+E- and placebo-treated groups. In conclusion, the present study supports the view that oxidative stress is involved in the pathogenesis of EH, and that enhancement of antioxidant status by supplementation with vitamins C and E in patients with EH is associated with lower BP. This suggests intervention with antioxidants as an adjunct therapy for hypertension.
Pius XII: romanità, prophesy and charisma
Authors: Logan Oliver 
Published: April 2008

Summary
The modern popular cult of the Pope, which originated with the ‘disinherited’ papacy of Pius IX, reached its acme with Pius XII. Phases of intensification of this cult, which was linked to other ‘devotions’, those of the Sacred Heart of Jesus and of the Virgin Mary, served to mobilize the Catholic masses at critical junctures for the Catholic Church and in the face of what were perceived as political threats. Pius XII had to animate ‘movement’ in an age proclaimed to be one of a unique crisis of civilization. The projection of him as a charismatic figure was linked to that of Rome as a sacred centre and as the very fulcrum of world history. The Catholic activist ethos of ‘movement’ and also the presentation of the interchange between Pius XII and the Crowd had features in common with Fascist rhetorics, but ultimately the cult of the ‘victim-Pope’ represented an inversion of the crasser forms of power-imagery.
Midkine and its clinical significance in endometrial carcinoma
Authors: Tanabe Kojiro , Matsumoto Mitsuyo , Ikematsu Shinya , Nagase Satoru , Hatakeyama Atsushi , Takano Tadao , Niikura Hitoshi , Ito Kiyoshi , Kadomatsu Kenji , Hayashi Shin‐ichi , Yaegashi Nobuo 
Published: April 2008

Midkine (MK) is a secreted heparin‐binding growth factor. Several types of human cancer have increased MK expression with elevated serum levels. The purpose of this study was to determine whether MK was expressed in endometrial carcinoma and to evaluate the clinicopathological significance of serum MK in patients with endometrial carcinoma. Immunohistochemical expression of MK was evaluated in 85 endometrial carcinoma samples and 33 controls. MK expression was significantly higher in the carcinomas than in normal endometrium (P < 0.001). Interestingly, MK expression was highest at the margins of invasion and low in the superficial areas of the tumor samples. Using ELISA, we compared serum MK concentration in 120 endometrial carcinoma patients with the concentration in 46 patients with benign gynecologic tumors. Serum MK value in patients with cancer was significantly higher than that in the patients with benign diseases (P = 0.01). Patients with positive lymph node metastasis or recurrence, or cancer death, had a higher serum MK level (P = 0.008,P = 0.009, respectively). In conclusion, MK immunoreactivity in endometrial carcinoma is significantly higher than in normal endometrium. Additionally, preoperative serum MK levels are significantly correlated with prognosis and the presence of lymph node metastasis. Thus, MK may be a useful serum biomarker for identifying high risk patients of endometrial carcinoma. (Cancer Sci2008; 99: 1125–1130)
Reduced risk of endometrial cancer from alcohol drinking in Japanese
Authors: Hosono Satoyo , Matsuo Keitaro , Kajiyama Hiroaki , Hirose Kaoru , Suzuki Takeshi , Hiraki Akio , Kawase Takakazu , Kidokoro Kumiko , Nakanishi Toru , Hamajima Nobuyuki , Kikkawa Fumitaka , Tajima Kazuo , Tanaka Hideo 
Published: April 2008

The role of alcohol consumption in the etiology of endometrial cancer has not been clarified. To examine the association between alcohol consumption and endometrial cancer risk, we conducted a case‐control study with 148 histologically diagnosed incident endometrial cancer cases and 1468 matched non‐cancer controls. Median consumption of alcohol was only 19.3 g/week among cases who drank and 28.2 g/week among controls who drank. These values are lower than in Western countries. Relative risk was analyzed in subjects classified into four groups according to weekly alcohol consumption (non‐drinkers, 1–24 g/week, 25–175 g/week, and >175 g/week). Confounder‐adjusted odds ratios for those consuming alcohol at <25 g/week, 25–175 g/week, and >175 g/week compared to non‐drinkers were 0.79 (95% confidence interval (CI), 0.49–1.28), 0.42 (95% CI, 0.23–0.79), and 0.47 (95% CI, 0.14–1.58), respectively. Further analysis was conducted concerning self‐reported physical reaction to alcohol. Among women without flushing after drinking, a significant inverse association between risk and alcohol intake was seen (trend P = 0.001). In contrast, no protective effect of alcohol was seen among women who experience flushing after drinking. These results suggest the presence of an inverse association between alcohol drinking and endometrial cancer risk among Japanese women, and that this association is evident among those without flushing. Further investigation of these findings is warranted. (Cancer Sci 2008; 99: 1195–1201)
Risk stratification and venous thromboprophylaxis in hospitalized medical and cancer patients
Authors: Prandoni Paolo , Samama Michel M. 
Published: April 2008

SummaryAcute venous thromboembolism (VTE) is a serious and potentially fatal disorder, which often complicates the course of hospitalized medical patients. This is particularly true for carriers of malignant diseases. While the introduction of thromboprophylactic measures has probably affected the occurrence of postoperative VTE, there is an increasing awareness of the importance of medical conditions in determining thromboembolic events. Simple and clinically relevant risk assessment models are available to facilitate VTE risk assessment in hospitalized medical patients. Their validation in prospective studies is in progress. Randomized controlled clinical trials have consistently documented the efficacy of heparins and fondaparinux for prevention of VTE in hospitalized medical patients with a minimal haemorrhagic risk. Recognition of the incidence and clinical importance of thrombosis will probably encourage more widespread use of antithrombotic prophylaxis in medical patients and especially in some particular types of malignancies.
Recent advances in the pathogenesis and management of juvenile myelomonocytic leukaemia
Authors: Koike Kenichi , Matsuda Kazuyuki 
Published: April 2008

SummaryJuvenile myelomonocytic leukaemia (JMML) is a fatal, mixed myeloproliferative and myelodysplastic disorder of early childhood. A number of significant advances have been achieved in recent years. The present review will focus on the pathogenesis and management of JMML. Specific defects in the RAS signalling pathway, which make JMML cells hypersensitive to granulocyte‐macrophage colony‐stimulating factor, are observed in at least two‐thirds of patients with JMML: inactivation of NF1 or mutations in NRAS, KRAS2 or PTPN11. Allogeneic haematopoietic stem cell transplantation is currently the only treatment able to cure JMML, although the high postrelapse rate is of great concern. We also review molecularly targeted therapeutics that interfere with the disrupted activation of the RAS signal transduction pathway.
Profilin sensitization detected in the office by skin prick test: a study of prevalence and clinical relevance of profilin as a plant food allergen
Authors: Asero R. , Monsalve R. , Barber D. 
Published: April 2008

SummaryBackground
Profilin, a pan‐allergen present in all eukaryotic cells, is one of the main causes of cross‐sensitization between pollen and plant‐derived foods, but its clinical relevance as a food allergen is still debated.Objective
To investigate the prevalence of profilin sensitization in a pollen‐allergic population and its clinical relevance as a food allergen.Methods
Two hundred consecutive patients with pollen allergy underwent skin prick tests (SPT) with purified natural date palm profilin (Pho d 2; 50 μg/mL; Alk Abello, Madrid, Spain). Those reporting adverse reactions to foods (confirmed by SPT with either commercial food extracts or fresh foods) underwent SPT with an apple extract containing uniquely Mal d 1 (2 μg/mL; ALK‐Abello), and with a commercial peach extract containing uniquely lipid transfer protein (LTP 30 μg/mL; ALK‐Abello).Results
Sixty patients (30%) showed skin reactivity to date palm profilin, Pho d 2. All were sensitized to grass pollen, and most of them reacted to birch, mugwort, ragweed and plantain pollen as well. SPT with pellitory and cypress scored negative in a high proportion of profilin reactors [26/60 (43%) and 33/60 (55%), respectively]. More than one half (34/60 [57%]) of profilin reactors had food allergy; 21 of these were monosensitized to profilin, 11 were sensitized to both profilin and Bet v 1 homologous protein, one to both profilin and LTP, and one to all the three allergens. The large majority of profilin‐allergic patients reported oral allergy syndrome as the only food‐induced symptom and were able to tolerate the offending foods if they were cooked or otherwise processed. Twenty‐eight of 34 reported reactivity to two or more plant‐derived foods. Rosaceae, tree nuts, melon and watermelon, tomato, pineapple, citrus fruits and banana were the more frequently offending foods.Conclusion
Profilin should be considered a clinically relevant food allergen. Allergy to melon, watermelon, tomato, banana, pineapple and orange may be considered as a marker of profilin hypersensitivity. This study underlines the clinical importance of being able to diagnose hypersensitivity to single food allergenic proteins by SPT, particularly when the relevant food allergen sources contain several allergens that show different chemical/physical features and, hence, completely different risk profiles.