bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of two distinct signalling pathways in IGF‐1‐mediated central control of hypotensive effects in normotensive and hypertensive rats
Authors: Cheng P.‐W. , Kang B.‐H. , Lu P.‐J. , Lin S.‐S. , Ho W.‐Y. , Chen H.‐H. , Hong L.‐Z. , Wu Y.‐S. , Hsiao M. , Tseng C.‐J. 
Published: July 2014

AbstractAimsInsulin‐like growth factor‐1 (IGF‐1) is abundantly expressed in the nucleus tractus solitarii (NTS). In a previous study, we revealed that the induction of nitric oxide (NO) production in the NTS reduces blood pressure (BP). It is well known that both acute administration and chronic administration of IGF‐I reduce BP. The aim of this study was to evaluate the short‐term hypotensive effect of IGF‐1 in the NTS and to delineate the underlying molecular mechanisms of IGF‐1 in the NTS of normotensive WKY rats and spontaneously hypertensive rats (SHRs).MethodMicroinjections of the phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002 and the MAP kinase‐ERK kinase (MEK) inhibitor PD98059 into the NTS in WKY rats and SHRs were used to study the involvement of IGF‐1‐induced depressor effects.ResultAn IGF‐1 (7.7 pmol) injection into the NTS resulted in a significant decrease in BP and HR in WKY rats and SHRs. Immunoblotting and immunohistochemical analysis showed that the microinjection of LY294002 (0.6 pmol) or PD98059 (3.0 pmol) into the NTS attenuated the IGF‐1‐induced depressor effects and Akt or ERK phosphorylation in WKY rats. An attenuation effect of LY294002, but not PD98059, was found in the SHRs. However, the mRNA and protein expression levels of the IGF‐1R showed no significant differences in the NTS of the WKY rats and the SHRs.ConclusionThese results suggest that distinct Akt and ERK signalling pathways mediated the IGF‐1 control of the central depressor effects in WKY rats and SHRs. ERK signalling defects may be associated with the development of hypertension.
Apelin‐13 and APJ in paraventricular nucleus contribute to hypertension via sympathetic activation and vasopressin release in spontaneously hypertensive rats
Authors: Zhang F. , Sun H.‐J. , Xiong X.‐Q. , Chen Q. , Li Y.‐H. , Kang Y.‐M. , Wang J.‐J. , Gao X.‐Y. , Zhu G.‐Q. 
Published: July 2014

AbstractAimsApelin is a specific endogenous ligand of orphan G protein‐coupled receptor APJ. This study was designed to determine the roles and mechanisms of apelin‐13 and APJ in paraventricular nucleus (PVN) in renal sympathetic nerve activity (RSNA), arginine vasopressin (AVP) release and mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR).MethodAcute experiment was carried out in 13‐week‐old male SHR and Wistar‐Kyoto rats (WKY) under anaesthesia. RSNA and MAP responses to the PVN microinjection were determined. Apelin and APJ expressions were examined with quantitative real‐time PCR and Western blot. AVP and noradrenaline were determined with ELISA. Osmotic minipumps were used for chronic PVN infusion in conscious WKY.ResultsApelin and APJ in the PVN were up‐regulated in SHR. The PVN microinjection of apelin‐13 increased, but APJ antagonist F13A decreased the RSNA, MAP, plasma noradrenaline and AVP levels in SHR. N‐methyl‐D‐aspartate receptor (NMDAR) antagonist plus non‐NMDAR antagonist abolished the apelin‐13‐induced sympathetic activation rather than AVP release. NMDAR antagonist or non‐NMDAR antagonist alone attenuated the apelin‐13‐induced sympathetic activation. Chronic infusion of apelin‐13 into the PVN in normotensive rats induced hypertension, increased plasma noradrenaline and AVP levels and promoted myocardial atrial natriuretic peptide and beta‐myosin heavy chain mRNA expressions, two indicative markers of cardiac hypertrophy.ConclusionApelin‐13 and APJ in the PVN contribute to hypertension via sympathetic activation and AVP release in SHR. The sympatho‐excitatory effect of apeline‐13 is mediated by both NMDAR and non‐NMDAR in the PVN. Persistent activation of APJ in the PVN induces hypertension.
A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers
Authors: Faruqi Shoaib , Wright Caroline , Thompson Rachel , Morice Alyn H. 
Published: July 2014

AimsThe examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin‐induced cough in healthy volunteers.MethodsIn this randomized, placebo‐controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre‐dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships.ResultsThirty‐four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate.ConclusionsWe have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses.
Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS
Authors: Zeidan Amer M. , Lee Ju‐Whei , Prebet Thomas , Greenberg Peter , Sun Zhuoxin , Juckett Mark , Smith Mitchell R. , Paietta Elisabeth , Gabrilove Janice , Erba Harry P. , Katterling Rhett P. , Tallman Martin S. , Gore Steven D. 
Published: July 2014

SummaryReliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.
Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia
Authors: Dandekar Smita , Romanos‐Sirakis Eleny , Pais Faye , Bhatla Teena , Jones Courtney , Bourgeois Wallace , Hunger Stephen P. , Raetz Elizabeth A. , Hermiston Michelle L. , Dasgupta Ramanuj , Morrison Debra J. , Carroll William L. 
Published: July 2014

SummaryWhile childhood acute lymphoblastic leukaemia (ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis‐relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analysed the expression of activated β‐catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of β‐catenin at relapse in 6/10 patients. Furthermore, treatment of leukaemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre‐treatment of purified blasts from patients with relapsed leukaemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt‐inhibition may be a promising therapeutic approach.
Differences in activities of daily living (ADL) abilities of children across world regions: a validity study of the assessment of motor and process skills
Authors: Gantschnig B. E. , Fisher A. G. , Page J. , Meichtry A. , Nilsson I. 
Published: July 2014

AbstractBackgroundOne important goal of paediatric occupational therapy services is to improve activities of daily living (ADL) abilities of children. In order to plan and evaluate the effectiveness of targeted interventions, valid assessments are critically needed. The Assessment of Motor and Process Skills (AMPS) is an internationally standardized assessment of ADL performance that has not been validated for use with children in Middle Europe.AimTo evaluate for (i) significant differences in mean ADL motor and mean ADL process ability measures among children from Middle Europe compared with children from North America, UK/Republic of Ireland, Nordic countries, Western Europe, Australia/New Zealand and Asia; and (ii) meaningful differences between the international age‐normative means of the AMPS and those for children from Middle Europe.MethodWe analysed data of children across world regions extracted from the international AMPS database using many‐facet Rasch and two‐way anova analyses and by estimating contrasts to evaluate for significant group differences.Resultsanova analyses of data for 11 189 children ages 2–15 revealed significant effects for mean ADL motor and ADL process ability by region [F ≥ 15.32, d.f. = (6, 11 091), MSE ≥ 0.20, P < 0.001, ή2 ≥ 0.008], and age [F ≥ 253.47, d.f. = (13, 11 091), MSE ≥ 0.20, P < 0.001, ή2 ≥ 0.229], and a significant interaction effect for mean ADL process ability [F = 1.48, d.f. = (78, 11 091), P = 0.004, ή2 = 0.010]. Out of 168 estimated contrasts between Middle Europe and the other world regions for mean ADL motor and ADL process ability, seven were statistically significant (4.17%), but none exceeded ±1SE from the international means.ConclusionThe AMPS remains free of relevant differences in mean ADL ability measures between Middle Europe and other world regions, indicating that the international age‐normative mean values are likely to be applicable to children from Middle Europe. The AMPS can be used internationally to evaluate ADL performance in children and to determine if the child is eligible for occupational therapy services.
The role of partial recording protocols in reporting prevalence and severity of dental fluorosis
Authors: Akinkugbe Aderonke , Iafolla Timothy , Chattopadhyay Amit , Garcia Isabel , Adams Amy , Kingman Albert 
Published: July 2014

AbstractObjectivesTo evaluate the role of partial recording protocols (PRPs) in reporting prevalence and severity of dental fluorosis and assess whether prevalence/severity estimates derived from PRPs differ by race/ethnicity.MethodsData from the National Health and Nutrition Examination Survey (NHANES) for the years 1999–2004 were analyzed with Stata® v.11. Prevalence of dental fluorosis obtained from a full‐mouth examination (28 teeth gold standard) was compared with estimates derived from four subsets of teeth (maxillary canine‐to‐canine; maxillary first‐premolar‐to‐first‐premolar; all‐premolars; all‐molars). Sensitivity, negative predictive value (NPV), absolute bias, and correction factors were calculated against gold standard estimate. Analysis was stratified according to race/ethnicity to assess differences in estimates derived from PRPs.ResultsAll subsets underestimated prevalence albeit to varying degrees. Two subsets (all‐premolars and all‐molars) had prevalence and severity estimates closest to gold standard estimates. The all‐molars subset (eight teeth) recorded the highest sensitivity (84.5%) and the lowest absolute bias (3.5%) of all subsets relative to gold standard. Subsets derived from esthetically relevant teeth produced the lowest fluorosis prevalence. For instance, the maxillary canine‐to‐canine subset underestimated prevalence by 9.5%; incorporating the maxillary first premolars in the span improved prevalence estimate by 31%. Among non‐Hispanic Whites, the all‐premolars subset produced estimates closest to gold standard while the all‐molars subset produced estimates closest to the gold standard among non‐Hispanic Blacks and Hispanics.ConclusionWhile the majority of dental fluorosis in the United States is very mild, concerns regarding its growing prevalence underscore the need for careful monitoring. The use of PRPs offers an alternative method of assessment, with validity of reported prevalence and severity dependent on choice of subset.
Unconventional apoptosis of polymorphonuclear neutrophils (PMN): staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by MΦ-2 macrophages of PMN
Authors: Franz S , Muñoz L E , Heyder P , Herrmann M , Schiller M 
Published: July 2014

Summary
Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent ‘silent’ removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis. PMN treated with STS underwent an unconventional form of cell death characterized by a delayed exposure of aminophospholipids, including phosphatidylserine (PS) and phosphatidylethanolamine and an increased exposure of neo-glycans. STS caused an impaired cellular fragmentation and accelerated DNA fragmentation. Phagocytosis of STS-treated PMN lacking PS on their surfaces was decreased significantly, which highlights the importance of PS for the clearance of apoptotic PMN. Specific opsonization with immune complexes completely restored phagocytosis of STS-treated PMN, demonstrating the efficiency of back-up clearance pathways in the absence of PS exposure.
Bacteria and their cell wall components uniformly co-activate interleukin-17-producing thymocytes
Authors: Weber A , Zimmermann C , Kieseier B C , Hartung H-P , Hofstetter H H 
Published: July 2014

SummaryInterleukin (IL)-17-producing T cells play a critical role in the immune response against microbial pathogens. Traditionally, experimental studies have focused upon understanding the activity of IL-17-producing T cells which differentiate from naive T cells in the peripheral immune system. However, we have demonstrated previously that IL-17-producing T cells are also present in the thymus of naive wild-type mice and can be co-activated there by microbial stimuli. Other studies have supported the concept that IL-17-producing thymocytes have a specific role in the immediate defence against microbial pathogens, which is independent from the development of an adaptive immune response. Given an important role of the thymus in systemic bacterial infection and sepsis, in this study we investigate the effect of a broad spectrum of bacteria and cell wall components on thymocyte cytokine production. Surprisingly, we find that all types of bacteria investigated (including non-pathogenic species) uniformly activate IL-17-producing thymocytes upon α-CD3 stimulation. In contrast, there is a heterogeneous effect on IL-6 and interferon (IFN)-γ-production with Gram-negative bacteria inducing far higher frequencies of IL-6- and IFN-γ-producing thymocytes than Gram-positive bacteria. We conclude that IL-17-producing thymocytes constitute a ‘first line of recognition’, but not a ‘first line of defence’ against bacteria in general. Their activity might lead to immune activation, but not necessarily to a pathological inflammatory disease condition. The difference between these two states might be determined by other immunological effector molecules, such as IL-6 and IFN-γ.
Role of adenosine receptors in resveratrol‐induced intraocular pressure lowering in rats with steroid‐induced ocular hypertension
Authors: Razali Norhafiza , Agarwal Renu , Agarwal Puneet , Kumar Sunil , Tripathy Minaketan , Vasudevan Sushil , Crowston Jonathan G , Ismail Nafeeza M 
Published: July 2014

AbstractBackgroundSteroid‐induced ocular hypertension is currently treated in the same way as primary open‐angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans‐resveratrol in rats with steroid‐induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans‐resveratrol.MethodsThe oculohypotensive effect of unilateral single‐drop application of various concentrations of trans‐resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid‐induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans‐resveratrol after pretreating animals with AR subtype‐specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein–ligand interaction, to determine the AR–trans‐resveratrol interaction.ResultsAll concentrations of trans‐resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans‐resveratrol 0.2%. In oculohypertensive rats, trans‐resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A1 antagonist abolished the oculohypotensive effect of trans‐resveratrol. Pretreatment with A3 and A2A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by trans‐resveratrol application in treated eyes. Computational studies showed that trans‐resveratrol has highest affinity for A2B and A1, followed by A2A and A3 AR.ConclusionTopically applied trans‐resveratrol reduces IOP in rats with steroid‐induced ocular hypertension. Trans‐resveratrol‐induced oculohypotension involves its agonistic activity at the A1 AR.
Management of diffuse ocular surface squamous neoplasia: efficacy and complications of topical chemotherapy
Authors: Rudkin Adam K , Dempster Lucy , Muecke James S 
Published: July 2014

AbstractBackgroundOcular surface squamous neoplasia (OSSN) characterized by diffuse conjunctival or corneal spread is much less common than localized conjunctival disease. However, it is an important subcategory of the disease because of the difficulty it poses to treatment. It is rarely amenable to simple excision, and a purely surgical approach usually necessitates ocular surface reconstruction. Primary treatment with topical chemotherapy is an alternative, but its efficacy for these lesions is not well understood.DesignRetrospective case series.ParticipantsThirty‐eight eyes treated for diffuse OSSN, defined as a lesion extending over five or more limbal clock hours or by extensive central or paracentral corneal spread.MethodsTreatment utilized either topical 5‐FU 1% or mitomycin‐C (MMC) 0.04%.Main Outcome Measures(i) Disease remission; (ii) complications.ResultsThirty‐two patients were treated for a primary diffuse OSSN. Ten patients (31%) required further treatment for disease persistence or recurrence. Thirteen patients had previously undergone a single unsuccessful treatment course for diffuse OSSN. Administration of a second treatment course (whether MMC or 5FU) was successful in 46% (six) of patients. 5‐FU 1% resulted in drug‐related complications in seven of 12 cases, and included a single case of focal paracentral corneal stromal melt. MMC 0.04% resulted in transient drug related complications in 23 of 39 cases.ConclusionDiffuse OSSN is often recalcitrant to initial treatment with either 5‐FU 1% or MMC 0.04%, and a pragmatic and vigilant approach to this heterogenous disease is required. Compared to localized disease, diffuse disease often requires multiple treatment efforts.
Are insertion torque and early osseointegration proportional? A histologic evaluation
Authors: Campos Felipe E. B. , Jimbo Ryo , Bonfante Estevam A. , Barbosa Darceny Z. , Oliveira Maiolino T. F. , Janal Malvin N. , Coelho Paulo G. 
Published: July 2014

AbstractObjectivesThe objective of this histologic study was to determine the effect of three drilling protocols (oversized, intermediate, and undersized) on biologic responses to a single implant type at early healing periods (2 weeks in vivo) in a beagle dog model.Materials and methodsTen beagle dogs were acquired and subjected to surgeries in the tibia 2 weeks before euthanasia. During surgery, each dog received three Unitite implants, 4 mm in diameter by 10 mm in length, in bone sites drilled to 3.5, 3.75, and 4.0 mm in final diameter. The insertion torque was recorded during surgery, and bone‐to‐implant contact (BIC), and bone area fraction occupied (BAFO) measured from the histology. Each outcome measure was compared between treatment conditions with the Wilcoxon signed‐rank test. Bonferroni‐corrected statistical significance was set to 95%.ResultsInsertion torque increased as an inverse function of drilling diameter, as indicated by significant differences in torque levels between each pair of conditions (P = 0.005). BIC and BAFO levels were highest and statistically similar in the recommended and undersized conditions and significantly reduced in the oversized condition (P < 0.01).ConclusionsReduced drilling dimensions resulted in increased insertion torque (primary stability). While BIC and BAFO were maximized when drilling the recommended diameter hole, only the oversized hole resulted in evidence of statistically reduced integration.