bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in the prevention of Alzheimer's disease and dementia
Authors: Solomon A. , Mangialasche F. , Richard E. , Andrieu S. , Bennett D. A. , Breteler M. , Fratiglioni L. , Hooshmand B. , Khachaturian A. S. , Schneider L. S. , Skoog I. , Kivipelto M. 
Published: March 2014

AbstractBackgroundDefinitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re‐examination. The shift towards presymptomatic and pre‐dementia stages of AD has brought prevention and treatment trials much closer to each other than before.MethodsHere we discuss: (i) the impact of diagnostic reliability on the possibilities for developing preventive strategies for AD; (ii) the scientific evidence to support moving from observation to action; (iii) ongoing intervention studies; and (iv) the methodological issues and prospects for balancing strategies for high‐risk individuals with those for broad population‐based prevention.ResultsThe associations between neuropathology and cognition are still not entirely clear. In addition, the risk factors for AD dementia and the neuropathological hallmarks of AD may not necessarily be the same. Cognitive impairment has a clearer clinical significance and should therefore remain the main focus of prevention. Risk/protective factors for dementia/AD need to be studied from a life‐course perspective. New approaches in prevention trials include enrichment strategies based on genetic risk factors or beta‐amyloid biomarkers (at least four ongoing pharmacological trials), and multidomain interventions simultaneously targeting various vascular and lifestyle‐related risk factors (at least three ongoing trials). Experience from prevention programmes in other chronic diseases can provide additional methodological improvements.ConclusionsBuilding infrastructures for international collaborations is necessary for managing the worldwide public health problem of AD and dementia. The International Database on Aging and Dementia (IDAD) and the European Dementia Prevention Initiative (EDPI) are examples of ongoing international efforts aiming to improve the methodology of preventive studies and provide the basis for larger intervention trials.
Mild cognitive impairment: a concept in evolution
Authors: Petersen R. C. , Caracciolo B. , Brayne C. , Gauthier S. , Jelic V. , Fratiglioni L. 
Published: March 2014

AbstractThe construct of mild cognitive impairment (MCI) has evolved over the past 10 years since the publication of the new MCI definition at the Key Symposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow‐up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population‐based studies on cognitive ageing and MCI need to be performed to clarify all these issues.
Clinical trials and late‐stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014
Authors: Schneider L. S. , Mangialasche F. , Andreasen N. , Feldman H. , Giacobini E. , Jones R. , Mantua V. , Mecocci P. , Pani L. , Winblad B. , Kivipelto M. 
Published: March 2014

AbstractThe modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late‐stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late‐stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta‐analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild‐to‐moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18‐ to 24‐month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early‐stage Alzheimer's disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late‐phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
Biomarkers: refining diagnosis and expediting drug development – reality, aspiration and the role of open innovation
Authors: Salter H. , Holland R. 
Published: March 2014

AbstractIn the last decade, there have been intensive efforts to invent, qualify and use novel biomarkers as a means to improve success rates in drug discovery and development. The biomarkers field is maturing and this article considers whether these research efforts have brought about the expected benefits. The characteristics of a clinically useful biomarker are described and the impact this area of research has had is evaluated by reviewing a few, key examples of emerging biomarkers. There is evidence that the impact has been genuine and is increasing in both the drug and the diagnostic discovery and development processes. Beneficial impact on patient health outcomes seems relatively limited thus far, with the greatest impact in oncology (again, both in terms of novel drugs and in terms of more refined diagnoses and therefore more individualized treatment). However, the momentum of research would indicate that patient benefits are likely to increase substantially and to broaden across multiple therapeutic areas. Even though this research was originally driven by a desire to improve the drug discovery and development process, and was therefore funded with this aim in mind, it seems likely that the largest impact may actually come from more refined diagnosis. Refined diagnosis will facilitate both better allocation of healthcare resources and the use of treatment regimens which are optimized for the individual patient. This article also briefly reviews emerging technological approaches and how they relate to the challenges inherent in biomarker discovery and validation, and discusses the role of public/private partnerships in innovative biomarker research.
Fatty acids and sleep in UK children: subjective and pilot objective sleep results from the DOLAB study – a randomized controlled trial
Authors: Montgomery Paul , Burton Jennifer R. , Sewell Richard P. , Spreckelsen Thees F. , Richardson Alexandra J. 
Published: March 2014

SummarySleep problems in children are associated with poor health, behavioural and cognitive problems, as are deficiencies of long‐chain omega‐3 fatty acids such as docosahexaenoic acid. Theory and some evidence support a role for these fatty acids in sleep regulation, but this issue has received little formal investigation. We examined associations between blood fatty acid concentrations (from fingerstick blood samples) and subjective sleep (using an age‐standardized parent questionnaire) in a large epidemiological sample of healthy children aged 7–9 years (n = 395) from mainstream UK schools. In a randomized controlled trial, we then explored whether 16‐week supplementation (600 mg day−1) with algal docosahexaenoic acid versus placebo might improve sleep in a subset of those children (n = 362) who were underperforming in reading. In a randomly selected subsample (n = 43), sleep was also assessed objectively via actigraphy. In 40% of the epidemiological sample, Child Sleep Habits Questionnaire scores indicated clinical‐level sleep problems. Furthermore, poorer total sleep disturbance scores were associated weakly but significantly with lower blood docosahexaenoic acid (std coeff. −0.105*) and a lower docosahexaenoic acid : arachidonic acid ratio (std coeff. −0.119**). The treatment trial showed no significant effects on subjective sleep measures. However, in the small actigraphy subsample, docosahexaenoic acid supplementation led on average to seven fewer wake episodes and 58 min more sleep per night. Cautiously, we conclude that higher blood levels of docosahexaenoic acid may relate to better child sleep, as rated by parents. Exploratory pilot objective evidence from actigraphy suggests that docosahexaenoic acid supplementation may improve children's sleep, but further investigations are needed.
Control of hypoglossal motoneurones during naturally occurring sleep and wakefulness in the intact, unanaesthetized cat: a field potential study
Authors: Fung Simon J. , Chase Michael H. 
Published: March 2014

SummaryThe present electrophysiological study was designed to determine the discharge threshold of hypoglossal motoneurones during naturally occurring states of sleep and wakefulness in the intact, unanaesthetized cat. The antidromic field potential, which reflects the net level of membrane excitability of motoneurones and therefore their discharge threshold, was recorded in the hypoglossal nucleus following stimulation of the hypoglossal nerve. The amplitude of the antidromic field potential was larger during wakefulness and non‐rapid eye movement (NREM) sleep compared with REM sleep. There was no significant difference in the amplitude of the field potential when wakefulness was compared with NREM sleep (P = 0.103, df = 3, t = 2.324). However, there was a 46% reduction in amplitude during REM sleep compared with NREM sleep (P < 0.001, df = 10, t = 6.421) or wakefulness (P < 0.01, df = 4, t = −4.598). These findings indicate that whereas the excitability of motoneurones that comprise the hypoglossal motor pool is relatively constant during wakefulness and NREM sleep, their excitability is significantly reduced during REM sleep. This state‐dependent pattern of control of hypoglossal motoneurones during REM sleep is similar to that reported for motoneurones in other motor nuclei at all levels of the neuraxis. The decrease in the evoked response of hypoglossal motoneurones, which reflects a significant increase in the discharge threshold of individual motoneurones, results in atonia of the lingual and related muscles during REM sleep.
A pharmacokinetic/clinical approach to postulate a local action of intra‐articular xylazine administration in the horse: a preliminary study
Authors: Di Salvo A. , Della Rocca G. , Bazzica C. , Giontella A. , Cagnardi P. , Nannarone S. 
Published: March 2014

The study aims to evaluate whether the analgesic effect of intra‐articular (IA) route of xylazine administered to horses following arthroscopic surgery is due to a local or a systemic action. Two connected studies were performed. In the first, 1 mg/kg b.w. of xylazine was injected IA, and blood samples were taken to assess drug systemic absorption. In addition, systemic effects of the drug (sedation, ataxia or reduction of respiratory and cardiac rate) were registered. Control horses injected with saline IA were included in the study to exclude the influence of anaesthesia in the occurrence of these manifestations. In the second study, 1 mg/kg b.w. of xylazine was administered intravenously (i.v.) in healthy horses. Blood samples were collected to determine the concentrations of xylazine, and the same signs of systemic effects of the drug were recorded. By correlating these parameters, a systemic ‘no effect’ concentration was defined. Pharmacokinetic data after IA administration resulted in some xylazine absorption (bioavailability equal to 58.12%) with values above the systemic ‘no effect’ concentration. The occurrence of some signs related to systemic effects in horses receiving IA xylazine was significant compared with horses receiving saline. In conclusion, a systemic action of the drug after IA administration cannot be excluded.
Postoperative hypoalbuminemia as a risk factor for surgical site infection after oral cancer surgery
Authors: Lee J‐I , Kwon M , Roh J‐L , Choi JW , Choi S‐H , Nam SY , Kim SY 
Published: March 2014

ObjectivesPostoperative surgical site infection (SSI) is a frequent postoperative complication in patients with oral cancer and significantly affects patient recovery and medical expenses. The aim of this study was to examine the predictors of SSI in patients undergoing major surgery for oral or oropharyngeal squamous cell carcinoma (OSCC) and to determine the relationship between perioperative albumin and the development of SSI.Subjects and methodsIn 337 consecutive patients who underwent clean‐contaminated surgery for OSCC, serum albumin, glucose, and hemoglobin levels were perioperatively measured. Differences between the groups were examined using Fisher's exact test, Mann–Whitney U‐test, and multiple logistic regression analysis.ResultsSurgical site infection was detected in 88 (26.1%) patients with median time to development of 10 (2–25) days. Multiple logistic regression analysis showed that only postoperative serum albumin < 2.5 g dl−1 was an independent variable predictive of SSI (P = 0.003). The duration of hospital stay was negatively correlated with postoperative albumin (R2 = –0.302, P < 0.001).ConclusionEarly postoperative hypoalbuminemia <2.5 g dl−1 is an independent risk factor for the development of SSI in patients undergoing oral cancer surgery. Clinicians should be aware of the implications of postoperative hypoalbuminemia and consider more intensive postoperative care in these patients.
Characterization of mesenchymal progenitor cells in crown and root pulp from human mesiodentes
Authors: Sato M , Toriumi T , Watanabe N , Watanabe E , Akita D , Mashimo T , Akiyama Y , Isokawa K , Shirakawa T , Honda MJ 
Published: March 2014

ObjectiveMesiodentes are usually found in the central position of the upper or lower jaw as supernumerary teeth. Here, we obtained 10 mesiodentes and three permanent teeth (PT) and separated the dental pulp (DP) from these into crown and root portions. We then characterized and compared the isolated crown portion‐derived cells (crown cells) with root portion‐derived cells (root cells) using a range of in vitro assays.Materials and methodsCrown cells and root cells were examined for cell surface marker expression, colony‐forming unit‐fibroblast (CFU‐F), cell proliferation, cell cycle characteristics and markers, and osteogenic and adipogenic differentiation.ResultsThe proportion of CD105‐positive cells (CD105+ cells) in the crown cells vs the root cells varied among the mesiodentes, but not among the PT. When there were more CD105+ cells in the root cells than in the crown cells, the root cells showed higher CFU‐F, proliferation capacity, and osteogenic differentiation capacity. In contrast, when the crown cells contained more CD105+ cells than the root cells, the crown cells showed the higher CFU‐F, proliferation capacity, and osteogenic differentiation capacity. In addition, the sorted CD105+ cells showed higher CFU‐F and proliferation capacity than the sorted CD105− cells.ConclusionThese results indicated that proportion of CD105+ cells is an effective means of characterizing DP‐derived cells in mesiodentes.
The Arabidopsis U11/U12‐65K is an indispensible component of minor spliceosome and plays a crucial role in U12 intron splicing and plant development
Authors: Jung Hyun Ju , Kang Hunseung 
Published: March 2014

SummaryThe U12‐dependent introns have been identified in a wide range of eukaryotes and are removed from precursor‐mRNAs by U12 intron‐specific minor spliceosome. Although several proteins unique to minor spliceosome have been identified, the nature of their effect on U12 intron splicing as well as plant growth and development remain largely unknown. Here, we characterized the functional role of an U12‐type spliceosomal protein, U11/U12‐65K in Arabidopsis thaliana. The transgenic knockdown plants generated by artificial miRNA‐mediated silencing strategy exhibited severe defect in growth and development, such as severely arrested primary inflorescence stems, serrated leaves, and the formation of many rosette leaves after bolting. RNA sequencing and reverse transcription polymerase chain reaction (RT‐PCR) analyses revealed that splicing of 198 out of the 234 previously predicted U12 intron‐containing genes and 32 previously unidentified U12 introns was impaired in u11/u12‐65k mutant. Moreover, the U11/U12‐65K mutation affected alternative splicing, as well as U12 intron splicing, of many introns. Microarray analysis revealed that the genes involved in cell wall biogenesis and function, plant development, and metabolic processes are differentially expressed in the mutant plants. U11/U12‐65K protein bound specifically to U12 small nuclear RNA (snRNA), which is necessary for branch‐point site recognition. Taken together, these results provide clear evidence that U11/U12‐65K is an indispensible component of minor spliceosome and involved in U12 intron splicing and alternative splicing of many introns, which is crucial for plant development.
Aid to the Services Sector: Does it Affect Manufacturing Exports?
Authors: Ferro Esteban , Portugal‐Perez Alberto , Wilson John S. 
Published: March 2014

AbstractThe authors evaluated the impact of foreign aid to five services sectors (transportation, information and communications technologies (ICT), energy, banking/financial services, and business services) on exports of downstream manufacturing sectors in developing countries. To address the reverse causality between aid and exports, they relied on an original identification strategy that exploits (i) the variation of aid flows to services sectors and (ii) the variation of service intensities across industrial sectors and countries using input–output data. They found a positive effect of aid to services, in general, on downstream manufacturing exports of developing countries across regions and income‐level groups.
Differential modulation of sympathetic and respiratory activities by cholinergic mechanisms in the nucleus of the solitary tract in rats
Authors: Furuya Werner I. , Bassi Mirian , Menani José V. , Colombari Eduardo , Zoccal Daniel B. , Colombari Débora S. A. 
Published: March 2014

New Findings
What is the central question of this study?
Is sympathorespiratory activity affected in a different manner by cholinergic mechanisms in the intermediate (iNTS) and commissural nucleus of the solitary tract (cNTS) and are cholinergic mechanisms involved in baro‐ and chemoreflexes?
What is the main finding and its importance?
Acetylcholine (ACh) injected into the iNTS promotes sympatho‐inhibition and reduces the phrenic frequency, whereas ACh injected into the cNTS increases phrenic frequency and affects sympathetic–respiratory coupling, without changing the sympathetic activity. These responses are abolished by mecamylamine (nicotinic antagonist) in the NTS. Mecamylamine in the cNTS also reduces peripheral chemoreflex‐induced tachypnoea.
The contribution of cholinergic mechanisms of the nucleus of the solitary tract (NTS) to cardiorespiratory control is not completely clear. In the present study, we investigated the involvement of the cholinergic mechanisms in the intermediate NTS (iNTS) and commissural NTS (cNTS) on the control of sympathetic (SNA) and phrenic nerve activity (PNA). Decorticated, arterially perfused in situ preparations of male juvenile rats (60–100 g) were used. Acetylcholine (10 mm, 60 nl) injected into the iNTS reduced SNA (−54 ± 4%, versus vehicle −5 ± 3%; P < 0.001) and PNA (−30 ± 4%, versus vehicle −5 ± 6%; P < 0.001), whereas injections of ACh into the cNTS increased PNA (30 ± 6%, versus vehicle 5 ± 3%; P < 0.001), without changing SNA. Pretreatment with mecamylamine (nicotinic antagonist; 5 mm) abolished all the effects of ACh injected into the iNTS or the cNTS, whereas atropine (muscarinic antagonist; 5 mm) reduced only the effects of ACh injected into the cNTS. Mecamylamine injected into the cNTS also reduced the tachypnoea in response to peripheral chemoreflex activation. The baroreflex was unaltered by injections of atropine or mecamylamine into the NTS. The results suggest that ACh and mainly nicotinic receptors in the NTS are involved in the modulation of SNA and PNA, with distinct functions between the iNTS and the cNTS. An involvement of the nicotinic receptors in the cNTS in the tachypnoea in response to peripheral chemoreflex activation is also suggested.