bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Prevents Osteopenia by Promoting Bone Formation and Suppressing Bone Resorption in Aged Ovariectomized Rats
Authors: Ma Xue , Meng Jingru , Jia Min , Bi Long , Zhou Ying , Wang Yukun , Hu Jing , He Gonghao , Luo Xiaoxing 
Published: February 2013

ABSTRACT

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal cross-linked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.
Risk factors for the development of vertebral fractures after percutaneous vertebroplasty
Authors: Martinez-Ferrer Angeles , Blasco Jordi , Carrasco Josep LI , Macho Juan M , Román Luis San , López Antonio , Monegal Ana , Guañabens Nuria , Peris Pilar 
Published: February 2013

ABSTRACT

We have recently observed an increased risk for vertebral fractures (VF) in a randomized controlled trial comparing the analgesic effect of vertebroplasty (VP) versus conservative treatment in symptomatic VF. The aim of the present study was to evaluate the risk factors related to the development of VF after VP in these patients. We evaluated risk factors including age, gender, bone mineral density, the number, type, and severity of vertebral deformities at baseline, the number of vertebral bodies treated, the presence and location of disk cement leakage, bone remodeling (determining bone turnover markers) and 25 hydroxyvitamin D [25(OH)D] levels at baseline in all patients. Twenty-nine radiologically new VF were observed in 17 of 57 patients undergoing VP, 72% adjacent to the VP. Patients developing VF after VP showed an increased prevalence of 25(OH)D deficiency (&lt;20 ng/mL) and higher P1NP values. The principal factor related to the development of VF after VP in multivariate analysis was 25(OH)D levels &lt; 20 ng/mL (RR, 15.47; 95% CI, 2.99–79.86, p &lt; 0.0001), whereas age &gt;80 years (RR, 3.20; 95% CI, 1.70–6.03, p = 0.0007) and glucocorticoid therapy (RR, 3.64; 95% CI, 1.61–8.26, p = 0.0055) constituted the principal factors in the overall study population. Increased risk of VF after VP was also associated with cement leakage into the inferior disk (RR, 6.14; 95% CI, 1.65–22.78, p = 0.044) and more than one vertebral body treated during VP (RR, 4.19; 95% CI, 1.03–34.3, p = 0.044). In conclusion, nearly 30% of patients with osteoporotic VF treated with VP had a new VF after the procedure. Age, especially &gt;80 years, the presence of inferior disk cement leakage after the procedure, the number of cemented vertebrae, and low 25(OH)D serum levels were related to the development of new VF in these patients, with the latter indicating the need to correct vitamin D deficiency prior to performing VP.
In Vivo Overexpression of Tissue-Nonspecific Alkaline Phosphatase Increases Skeletal Mineralization and Affects the Phosphorylation Status of Osteopontin
Authors: Narisawa Sonoko , Yadav Manisha C , Millán José Luis 
Published: February 2013

ABSTRACT

Functional ablation of tissue-nonspecific alkaline phosphatase (TNAP) (Alpl−/− mice) leads to hypophosphatasia, characterized by rickets/osteomalacia attributable to elevated levels of extracellular inorganic pyrophosphate, a potent mineralization inhibitor. Osteopontin (OPN) is also elevated in the plasma and skeleton of Alpl−/− mice. Phosphorylated OPN is known to inhibit mineralization, however, the phosphorylation status of the increased OPN found in Alpl−/− mice is unknown. Here, we generated a transgenic mouse line expressing human TNAP under control of an osteoblast-specific Col1a1 promoter (Col1a1-Tnap). The transgene is expressed in osteoblasts, periosteum, and cortical bones, and plasma levels of TNAP in mice expressing Col1a1-Tnap are 10 to 20 times higher than those of wild-type mice. The Col1a1-Tnap animals are healthy and exhibit increased bone mineralization by micro–computed tomography (µCT) analysis. Crossbreeding of Col1a1-Tnap transgenic mice to Alpl−/− mice rescues the lethal hypophosphatasia phenotype characteristic of this disease model. Osteoblasts from [Col1a1-Tnap] mice mineralize better than nontransgenic controls and osteoblasts from [Col1a1-Tnap+/−; Alpl−/−] mice are able to mineralize to the level of Alpl+/− heterozygous osteoblasts, whereas Alpl−/− osteoblasts show no mineralization. We found that the increased levels of OPN in bone tissue of Alpl−/− mice are comprised of phosphorylated forms of OPN whereas wild-type (WT) and [Col1a1-Tnap+/−; Alpl−/−] mice had both phosphorylated and dephosphorylated forms of OPN. OPN from [Col1a1-Tnap] osteoblasts were more dephosphorylated than nontransgenic control cells. Titanium dioxide-liquid chromatography and tandem mass spectrometry analysis revealed that OPN peptides derived from Alpl−/− bone and osteoblasts yielded a higher proportion of phosphorylated peptides than samples from WT mice, and at least two phosphopeptides, p(S174FQVS178DEQY182PDAT186DEDLT191)SHMK and FRIp(S299HELES304S305S306S307)EVN, with one nonlocalized site each, appear to be preferred sites of TNAP action on OPN. Our data suggest that the promineralization role of TNAP may be related not only to its accepted pyrophosphatase activity but also to its ability to modify the phosphorylation status of OPN.
A Decision‐Analysis Tool for Benefit–Risk Assessment of Nonprescription Drugs
Authors: Brass Eric P. , Lofstedt Ragnar , Renn Ortwin 
Published: February 2013

AbstractA decision analysis tool is proposed for regulatory assessment of nonprescription drugs. The tool is based on evaluation of each of the drug's potential benefit and risk attributes identified using a value‐tree framework. The decision tool is designed as two‐factor, two‐stage instrument. Each attribute is independently assessed based on both the frequency of occurrence and clinical impact of the attribute. Frequency and clinical impact are scored on a 0–3 scale where a 0 score means no occurrence or no clinical impact, and a 3 means high frequency of occurrence or high clinical impact. The tool is initially used early in drug development to facilitate communication amongst stakeholders and to identify important data gaps. After new data are generated during the development program the tool is used again across the same attributes to yield a final benefit–risk assessment. In both the early assessment and subsequent evaluation use of the Group‐Delphi technique and a benefit–risk trade‐off heuristic may yield more consistent and coherent outputs. The tool allows regulators to maintain flexibility with respect to how final decisions are made, yet allows specificity and transparency during the evaluation. Further modifications can be incorporated to address drug‐specific requirements or regulatory preferences.
The Antibody Drug Absorption Following Subcutaneous or Intramuscular Administration and Its Mathematical Description by Coupling Physiologically Based Absorption Process with the Conventional Compartment Pharmacokinetic Model
Authors: Zhao Liang , Ji Ping , Li Zhihong , Roy Partha , Sahajwalla Chandrahas G. 
Published: February 2013

AbstractThe main objective of this paper is to propose a quantitative model to describe the absorption process for monoclonal antibody (mAb) following subcutaneous (SC) or intramuscular (IM) administration. A hybrid model was established by coupling the physiologically based absorption process with a conventional pharmacokinetic–pharmacodynamic (PK–PD) or PK model associated with intravenous infusion. Key physiological parameters evaluated include the volume distribution before systemic absorption, mAb drug clearance during lymphatic transport, the neonatal Fc receptor (FcRn) capacity, the intrinsic drug clearance via lysosomal proteolytic process, and the lymphatic flow rate. Sensitivity analyses were performed to identify those physiological parameters significantly impacting time to peak concentration (Tmax) or drug bioavailability. Simulation results showed that lymphatic flow rate is the only influential factor to Tmax. Lymphatic transit time and drug clearance during lymphatic transport are most influential to bioavailability but not identifiable in their effects. Bioavailability is positively related to the lymphatic flow only at its low range (i.e., at <0.5‐fold of the selected value of 0.043 mL/min). The rest of physiological parameters only have marginal effects on either drug bioavailability or Tmax. Finally, simulation results confirmed lymphatic transport as the major route of mAb delivery.
Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p‐Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs
Authors: Ieiri Ichiro , Tsunemitsu Shyohei , Maeda Kazuya , Ando Yukie , Izumi Noritomo , Kimura Miyuki , Yamane Naoe , Okuzono Tsuyoshi , Morishita Mariko , Kotani Naoki , Kanda Eri , Deguchi Mariko , Matsuguma Kyoko , Matsuki Shunji , Hirota Takeshi , Irie Shin , Kusuhara Hiroyuki , Sugiyama Yuichi 
Published: February 2013

AbstractWe investigated the mechanisms of ritonavir‐mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p‐glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC–MS/MS methods. The mean plasma AUC0–24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration‐time curve (AUC)0–24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01–.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A‐mediated metabolism, and intestinal p‐glycoprotein‐mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.
Solutions of the stream power equation and application to the evolution of river longitudinal profiles
Authors: Royden Leigh , Taylor Perron J. 
Published: February 2013

AbstractErosion by bedrock river channels is commonly modeled with the stream power equation. We present a two‐part approach to solving this nonlinear equation analytically and explore the implications for evolving river profiles. First, a method for non‐dimensionalizing the stream power equation transforms river profiles in steady state with respect to uniform uplift into a straight line in dimensionless distance‐elevation space. Second, a method that tracks the upstream migration of slope patches, which are mathematical entities that carry information about downstream river states, provides a basis for constructing analytical solutions. Slope patch analysis explains why the transient morphology of dimensionless river profiles differs fundamentally if the exponent on channel slope, n, is less than or greater than one and why only concave‐up migrating knickpoints persist when n < 1, whereas only concave‐down migrating knickpoints persist when n > 1. At migrating knickpoints, slope patches and the information they carry are lost, a phenomenon that fundamentally limits the potential for reconstructing tectonic histories from bedrock river profiles. Stationary knickpoints, which can arise from spatially varying uplift rates, differ from migrating knickpoints in that slope patches and the information they carry are not lost. Counterparts to migrating knickpoints, called “stretch zones,” are created when closely spaced slope patches spread to form smooth curves in distance‐elevation space. These theoretical results are illustrated with examples from the California King Range and the Central Apennines.
Reduction of the temperature sensitivity of minerotrophic fen methane emissions by simulated glacial atmospheric carbon dioxide starvation
Authors: Boardman Carl P. , Gauci Vincent , Fox Andrew , Blake Stephen , Beerling David J. 
Published: February 2013

AbstractVariations to the global wetland CH4 source strength in response to changes in orbital insolation patterns and atmospheric CO2 concentration ([CO2]a) are hypothesized to play an important role in determining glacial‐interglacial variations in atmospheric CH4 concentration ([CH4]a). Here the interactive effects of temperature, a major controlling variable determining wetland CH4 flux, and the low [CO2]a of glacial intervals are investigated for the first time. We measured the temperature dependence of CH4 emissions from replicated mesocosms (n = 8 per CO2 treatment) collected from a minerotrophic fen and an ombrotrophic bog incubated in either ambient (c. 400 ppm) or glacial (c. 200 ppm) [CO2]a located in the United Kingdom. CH4 fluxes were measured at 5°C, 10°C, 15°C, 20°C, and 25°C and then in reverse order over a 20 day period under each [CO2]a treatment. Results showed that the Q10 temperature response of CH4 emissions from the Carex/Juncus‐dominated fen declined significantly by approximately 39% under glacial [CO2]a (ambient [CO2]a = 2.60, glacial [CO2]a = 1.60; P < 0.01). By contrast, the response of CH4 emissions from the Sphagnum‐dominated bog remained unaltered (ambient [CO2]a = 3.67, glacial [CO2]a = 3.67; P > 0.05). This contrasting response may be linked to differences in plant species assemblage and the varying impact of CO2 starvation on plant productivity and carbon availability in the rhizosphere. Furthermore, our results provide empirical evidence to support recent model‐based indications that glacial‐interglacial variations in [CH4]a may be explained by changes in wetland CH4 source strength in response to orbitally forced changes in climate and [CO2]a.
The relationships between consumer liking, sensory and chemical attributes of Vitis vinifera L. cv. Pinotage wines elaborated with different Oenococcus oeni starter cultures
Authors: Malherbe Sulette , Menichelli Elena , du Toit Maret , Tredoux Andreas , Muller Nina , Næs Tormod , Nieuwoudt Hélène 
Published: February 2013

AbstractBackgroundMalolactic fermentation (MLF) mediated by lactic acid bacteria (LAB) has been shown to modulate chemical and sensory attributes of wine. This study investigated the relation between consumer liking, chemical and sensory attributes of Vitis vinifera L. cv. Pinotage wines that were made over two vintages by four different lactic acid Oenococcus oeni starter cultures as well as a control treatment where MLF was prevented.ResultsDescriptive analysis showed that the sensory attributes buttery, caramel, vegetative flavour, fruity and nutty aroma differed significantly between the wines. These effects on the wines were not the same for the two vintages tested. Preference mapping results showed that the sensory attributes influenced the average consumer liking. The main chemical and sensory correlations found for MLF‐treated wines were related to 2,3‐butanedione (diacetyl) with the buttery character and various esters with fruity aromas.ConclusionAlthough the direct effect of the bacterial starter cultures on wine sensory attributes is difficult to establish, and subject to variation over vintage, the present work suggests that the contribution of LAB starter cultures to wine sensory attributes can influence consumer liking. Selection of an MLF starter culture can thus potentially be used to develop specific wine styles. © 2013 Society of Chemical Industry
18F‐FDG‐PET/CT for the Assessment of the Contralateral Neck in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Kastrinidis Nikos , Kuhn Felix P. , Hany Thomas F. , Ahmad Nader , Huber Gerhard F. , Haerle Stephan K. 
Published: February 2013

Objectives/HypothesisThe aim was to compare the value of 18‐Fluoro‐Deoxyglucose (18F‐FDG) positron emission tomography (PET)/computed tomography (CT) regarding contralateral lymph node (LN) metastasis in the neck.Study DesignRetrospective analysis of 61 patients staged by 18F‐FDG‐PET/CT.MethodsCytology/histology served as a reference standard. Further, metabolic midline invasion (MI) of the primary tumor and the presence of bilateral LN metastases were assessed.ResultsA true positive rate in the ipsilateral neck of 80% versus 65% in the contralateral neck was found (P = 0.067). Median‐standardized uptake value (SUV)‐max for suspicious LN ipsilaterally was 7.6 versus 5.8 contralaterally (P = 0.038). There was no positive correlation between metabolic MI and bilateral metastasis (P = 0.82).ConclusionsThe rate of true positive detected LN by 18F‐FDG‐PET/CT is less on the contralateral neck side; therefore, all suspicious LNs should be verified by cytology. A high SUV in the contralateral neck suggests metastatic disease regardless of nodal size. Metabolic MI needs to be addressed carefully as it was not predictive for bilateral LN involvement.Level of Evidence4.
Bladder dysfunction in a transgenic mouse model of multiple system atrophy
Authors: Boudes Mathieu , Uvin Pieter , Pinto Silvia , Voets Thomas , Fowler Clare J. , Wenning Gregor K. , De Ridder Dirk , Stefanova Nadia 
Published: February 2013

ABSTRACTMultiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA. © 2013 Movement Disorder Society
Roles of mouse sperm‐associated alpha‐L‐fucosidases in fertilization
Authors: Phopin Kamonrat , Nimlamool Wutigri , Lowe‐Krentz Linda J. , Douglass Elijah W. , Taroni Jaclyn N. , Bean Barry S. 
Published: February 2013

AbstractSperm‐associated α‐L‐fucosidases have been implicated in fertilization in many species. Previously, we documented the existence of α‐L‐fucosidase in mouse cauda epididymal contents, and showed that sperm‐associated α‐L‐fucosidase is cryptically stored within the acrosome and reappears within the sperm equatorial segment after the acrosome reaction. The enrichment of sperm membrane‐associated α‐L‐fucosidase within the equatorial segment of acrosome‐reacted cells implicates its roles during fertilization. Here, we document the absence of α‐L‐fucosidase in mouse oocytes and early embryos, and define roles of sperm associated α‐L‐fucosidase in fertilization using specific inhibitors and competitors. Mouse sperm were pretreated with deoxyfuconojirimycin (DFJ, an inhibitor of α‐L‐fucosidase) or with anti‐fucosidase antibody; alternatively, mouse oocytes were pretreated with purified human liver α‐L‐fucosidase. Five‐millimolar DFJ did not inhibit sperm–zona pellucida (ZP) binding, membrane binding, or fusion and penetration, but anti‐fucosidase antibody and purified human liver α‐L‐fucosidase significantly decreased the frequency of these events. To evaluate sperm‐associated α‐L‐fucosidase enzyme activity in post‐fusion events, DFJ‐pretreated sperm were microinjected into oocytes, and 2‐pronuclear (2‐PN) embryos were treated with 5 mM DFJ with no significant effects, suggesting that α‐L‐fucosidase enzyme activity does not play a role in post‐fusion events and/or early embryo development in mice. The recognition and binding of mouse sperm to the ZP and oolemma involves the glycoprotein structure of α‐L‐fucosidase, but not its catalytic action. These observations suggest that deficits in fucosidase protein and/or the presence of anti‐fucosidase antibody may be responsible for some types of infertility. Mol. Reprod. Dev. 80: 273–285, 2013. © 2013 Wiley Periodicals, Inc.
Möglichkeiten und Grenzen der Lichterzeugung
Authors: Kauer E. , Schnedler E. 
Published: February 2013

AbstractVor mehr als 100 Jahren wurde die elektrische Glühlampe durch Edison in breitem Umfang eingeführt. Diese bahnbrechende Innovation war nicht nur der Anfang der modernen Lichterzeugung, sondern auch der unseres elektrotechnischen Zeitalters. Der Weg der Lichterzeugung, der mit Edisons Kohlefadenlampe begann, ist von Anbeginn an vom Wunsch nach Energieeinsparung, d. h. nach höherer Lichtausbeute, gekennzeichnet.
Metalle mit Gedächtnis: Phänomene, Anwendungen und Simulation eines Materialverhaltens
Authors: Müller I. 
Published: February 2013

AbstractDas Last‐Dehnungs‐Temperaturverhalten von Gedächtnislegierungen beruht auf einem Zusammenwirken von Zwillingsbildung im Metallgitter bei niedriger Temperatur und dem Übergang zu einer hochsymmetrischen Phase bei hoher Temperatur. Es kommt zu rückstellbaren Dehnungen von bis zu zehn Prozent in einem Temperaturintervall von ca. 30°C. Anwendungsmöglichkeiten ergeben sich für thermisch aktivierte Stellglieder, in der Medizin und bei thermisch‐mechanischer Energieumwandlung.