bluuebunny/crossref_metadata_2025 huggingface dataset:
Deformation of Ancient Buildings inferred by Terrestrial Laser Scanning methodology: the Cantalovo church case study (Northern Italy)*
Authors: Bonali E. , Pesci A. , Casula G. , Boschi E.
Published: March 2013

The study of the health of a building connects humanistic and scientific research, and a complete characterization can be achieved by integrating all the available historical documentation, architectural and metrological studies, as well as laboratory and in situ analyses of the materials. A contactless, non‐invasive surveying technique such as terrestrial laser scanning (TLS) allows the acquisition of dense and accurate geometric and radiometric (electromagnetic measurements such as signal intensity) information about the observed surface of the building, which can be easily integrated with data provided by high‐resolution digital imaging. The early Christian Cantalovo church was surveyed for the first time in April 2011, by means of the ILRIS‐3D ER very long range scanner. The second and last survey was performed in June 2012, after the main shocks of the Emilia earthquake seismic sequence. A very long range instrument is suitable for fast, simple and independent measurements, due to its technical characteristics and, for this reason, is easily usable for accurate surveying in emergency conditions. The main results are obtained by applying a data analysis strategy based on the creation of TLS‐based morphological maps computed as point‐to‐primitive differences, which allow the creation of a deformation map and its evolution in time.
Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects
Authors: Upreti Vijay V. , Wang Jessie , Barrett Yu Chen , Byon Wonkyung , Boyd Rebecca A. , Pursley Janice , LaCreta Frank P. , Frost Charles E.
Published: March 2013

Aim

Apixaban is an oral, direct, factor‐Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non‐valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability.

Method

Fifty‐four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65–85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti‐factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored.

Results

Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8–51%] and 20% (90% CI: 11–42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18–41%) and 23% (90% CI: 9–35%) lower apixaban Cmax and AUC(0,∞), respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti‐factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study.

Conclusion

The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.
Citronellol Reduces Orofacial Nociceptive Behaviour in Mice – Evidence of Involvement of Retrosplenial Cortex and Periaqueductal Grey Areas
Authors: Brito Renan G. , Santos Priscila L. , Prado Douglas S. , Santana Marília T. , Araújo Adriano A. S. , Bonjardim Leonardo R. , Santos Márcio R. V. , de Lucca Júnior Waldecy , Oliveira Aldeídia P. , Quintans‐Júnior Lucindo J.
Published: March 2013

Citronellol (CT) is a monoterpenoid alcohol present in the essential oil of many medicinal plants, such as Cymbopogon citratus. We evaluated the antinociceptive effects of CT on orofacial nociception in mice and investigated the central pathway involved in the effect. Male Swiss mice were pretreated with CT (25, 50 and 100 mg/kg, i.p.), morphine (5 mg/kg, i.p.) or vehicle (saline + tween 80 0.2%). Thirty minutes after the treatment, we injected formalin (20 μl, 2%), capsaicin (20 μl, 2.5 μg) or glutamate (40 μl, 25 μM) into the right limb. For the action in the CNS, ninety minutes after the treatment, the animals were perfused, the brains collected, crioprotected, cut in a criostate and submitted in an immunofluorescence protocol for Fos protein. CT produced significant (p < 0.01) antinociceptive effect, in all doses, in the formalin, capsaicin and glutamate tests. The immunofluorescence showed that the CT activated significantly (p < 0.05) the olfactory bulb, the piriform cortex, the retrosplenial cortex and the periaqueductal grey of the CNS. Together, our results provide first‐time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey.
Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats
Authors: Reyes‐Esparza Jorge , Mendoza‐Rivera Brissa , De la Cruz‐Cordero Ricardo , Rosado Jorge L. , Duarte‐Vázquez Miguel Á. , Solis Mario G. , Vite‐Vallejo Odón , Rodríguez‐Fragoso Lourdes
Published: March 2013

In this study, we evaluated the effect of an analogue of l‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l‐carnitine and improves the pharmacological profile of l‐carnitine.
The Influence of Oral Antidiabetic Drugs on Cellular Drug Uptake Mediated by Hepatic OATP Family Members
Authors: Klatt Sabine , Fromm Martin F. , König Jörg
Published: March 2013

As patients with type 2 diabetes receiving oral antidiabetic drugs are often concomitantly treated with other drugs, they are of increased risk for drug interactions. Drugs have to be taken up into hepatocytes before their intracellular drug action or before they are metabolized, and therefore, uptake transporters are important modulators of drug pharmacokinetics and drug effects. To gain more insights into the role of uptake transporters for drug interactions, we investigated whether frequently prescribed oral antidiabetic drugs interact with the transport of drugs, mediated by the hepatic uptake transporters OATP1B1 (gene symbol SLCO1B1), OATP1B3 (gene symbol SLCO1B3) and OATP2B1 (gene symbol SLCO2B1). Using HEK293 cells recombinantly over‐expressing these uptake transporters, we analysed whether glibenclamide, glimepiride, nateglinide and pioglitazone influence the transport of the model transport substrate bromosulfophthalein. Furthermore, we investigated the influence of the same oral antidiabetic drugs and of repaglinide and rosiglitazone on the uptake of the HMG‐CoA‐reductase inhibitor atorvastatin. The oral antidiabetic drugs glibenclamide, glimepiride and nateglinide inhibited the transport of the model substrate bromosulfophthalein, particularly the OATP2B1‐mediated uptake. The OATP‐mediated atorvastatin uptake was inhibited in a similar manner. For glibenclamide, inhibitory constants (Ki values) of 13.6 μM, 8.1 μM and 0.5 μM for OATP1B1‐, OATP1B3‐ and OATP2B1‐mediated BSP uptake were determined. In conclusion, these in vitro results demonstrate that several oral antidiabetic drugs may influence hepatic OATP‐mediated drug uptake. The in vivo consequences of these results have to be analysed in further studies.
Who Is Well After Childbirth? Factors Related to Positive Outcome
Authors: Henderson Jane , Redshaw Maggie
Published: March 2013

Background

Poor outcomes after childbirth are associated with physical ill health and with an absence of a positive sense of well‐being. Postnatally poor physical health is thought to be influenced by the care received, the nature of the birth, and associated complications. The aim of this study was to estimate the effects of a range of clinical and other factors on positive outcome and well‐being 3 months after childbirth.

Methods

This study used data on more than 5,000 women from a 2010 National Maternity Survey about their experiences of maternity care, and health and well‐being 3 months after childbirth. Positive outcome was defined as women reporting no problems and feeling “very well” at the time of the survey.

Results

In the univariate analysis, several variables were significantly associated with positive outcome, including sociodemographic, antenatal, intrapartum, and postnatal factors. In the final logistic regression model, young mothers, those without physical disability and those with no or few antenatal or early postnatal problems, were most likely to have positive outcomes. Other significant factors included a positive initial reaction to the pregnancy, not reporting antenatal depression, fewer worries about the labor and birth, and access to information about choices for care.

Conclusions

This study shows how positive outcomes for women after childbirth may be influenced by health, social, and care factors. It is important for caregivers to bear these factors in mind so that extra support may be made available to those women who are likely to be susceptible to poor outcome. (BIRTH 40:1 March 2013)
Association of Health Profession and Direct‐to‐Consumer Marketing with Infant Formula Choice and Switching
Authors: Huang Yi , Labiner‐Wolfe Judith , Huang Hui , J. Choiniere Conrad , Fein Sara B.
Published: March 2013

Background

Infant formula is marketed by health professionals and directly to consumers. Formula marketing has been shown to reduce breastfeeding, but the relation with switching formulas has not been studied. Willingness to switch formula can enable families to spend less on formula.

Methods

Data are from the Infant Feeding Practices Study II, a United States national longitudinal study. Mothers were asked about media exposure to formula information during pregnancy, receiving formula samples or coupons at hospital discharge, reasons for their formula choice at infant age 1 month, and formula switching at infant ages 2, 5, 7, and 9 months. Analysis included 1,700 mothers who fed formula at infant age 1 month; it used logistic regression and longitudinal data analysis methods to evaluate the association between marketing and formula choice and switching.

Results

Most mothers were exposed to both types of formula marketing. Mothers who received a sample of formula from the hospital at birth were more likely to use the hospital formula 1 month later. Mothers who chose formula at 1 month because their doctor recommended it were less likely to switch formula than those who chose in response to direct‐to‐consumer marketing. Mothers who chose a formula because it was used in the hospital were less likely to switch if they had not been exposed to Internet web‐based formula information when pregnant or if they received a formula sample in the mail.

Conclusions

Marketing formula through health professionals may decrease mothers' willingness to switch formula. (BIRTH 40:1 March 2013)
Depressive Symptoms in New First‐Time Fathers: Associations with Age, Sociodemographic Characteristics, and Antenatal Psychological Well‐Being
Authors: Bergström Malin
Published: March 2013

Background

New fathers may be as vulnerable as new mothers to depression, and their symptoms also can affect the mother and child. The purpose of this study was to investigate depressive symptoms and associations with paternal age, sociodemographic characteristics, and antenatal psychological well‐being in Swedish first‐time fathers.

Methods

Depressive symptoms, defined as scores of 11 or greater on the Edinburgh Postnatal Depression Scale, were investigated in 812 men 3 months after their first baby was born. The study sample included primarily Swedish‐born, married or cohabiting men who participated in antenatal education classes during the partner's pregnancy.

Results

In all, 10.3 percent of study men suffered from depressive symptoms. Compared with fathers aged 29–33 years (sample mean age ± 2 yr), the younger fathers had an increased risk for depressive symptoms (OR 2.55; 95% CI 1.50–4.35). Low educational level, low income, poor partner relationship quality, and financial worry increased the risk for depressive symptoms, but these factors could not explain the increased risk among the young.

Conclusions

New fathers in their twenties seem to have an increased risk for depressive symptoms that cannot be explained solely by socioeconomic factors. Support should be offered to new fathers with particular focus on the young. (BIRTH 40:1 March 2013)
Chewing gum moderates the vigilance decrement
Authors: Morgan Kate , Johnson Andrew J. , Miles Christopher
Published: March 2013

We examine the impact of chewing gum on a Bakan‐type vigilance task that requires the continual updating of short‐term order memory. Forty participants completed a 30‐min auditory Bakan‐task either with, or without, the requirement to chew gum. Self‐rated measures of mood were taken both pre‐ and post‐task. As expected, the vigilance task produced a time‐dependent performance decrement indexed via decreases in target detections and lengthened correct reaction times (RTs), and a reduction in post‐task self‐rated alertness scores. The declines in both performance and subjective alertness were attenuated in the chewing‐gum group. In particular, correct RTs were significantly shorter following the chewing of gum in the latter stages of the task. Additionally, the gradients of decline for target detection and incline for correct RTs were both attenuated for the chewing‐gum group. These findings are consistent with the data of Tucha and Simpson (2011), Appetite, 56, 299–301, who showed beneficial effects of chewing gum in the latter stages of a 30 min visual attention task, and extend their data to a task that necessitates the continuous updating of order memory. It is noteworthy that our data contradict the claim (Kozlov, Hughes, & Jones, 2012, Q. J. Exp. Psychology, 65, 501–513) that chewing gum negatively impacts short‐term memory task performance.
The Death of the Author through False Translation in Mario Bellatin's Orientalised Japan
Authors: LÓPEZ‐CALVO IGNACIO
Published: March 2013

This article argues that Mario Bellatin's exploration of the potential relationship between writing, translation and physical deformity leads, perhaps unconsciously, to the continuation of exoticising stereotypes about ‘Oriental’ cultures. In El jardín de la señora Murakami, Shiki Nagaoka: una nariz de ficción, and Biografía ilustrada de Mishima, Bellatin resorts to Japanese characters to distance himself from his own writings, as if it were the culture that is the most alien to his own. His lucubrations about reading and writing are sometimes accompanied of exocitising and orientalist overtones, which he mocks at times.
Palaeoenvironment in northern Norway between 22.2 and 14.5 cal. ka BP
Authors: Vorren Tore O. , Vorren Karl‐Dag , Aasheim Odd , Dahlgren K. I. Torbjørn , Forwick Matthias , Hassel Kristian
Published: March 2013

The stratigraphy of lake Endletvatn on northern Andøya, northern Norway, has been revisited to improve the understanding of the palaeoenvironment in the region during the Last Glacial Maximum (LGM). Four high‐quality cores were analysed with respect to various lithological parameters and macrofossil content, supplemented by 47 AMS radiocarbon dates. The sediments indicate a low‐energy environment with a mean sedimentation rate of 0.5 mm a−1. We infer perennially frozen ground in the surroundings during the LGM. Climate proxies indicate a high arctic climate (i.e. July mean temperatures between 0 and 3°C) throughout most of the LGM. The warmest periods are marked by a rise in seed, moss and animal fossils, and often also by higher organic production in the lake. These periods took place from 21.4 to 20.1, from 18.8 to 18.1, around 17 and from 16.4 cal. ka BP onwards. The shifts between the different climatic regimes occurred rapidly – probably during one or two decades. The present data do not support recently published conclusions stating that Picea, Pinus and Betula pubescens grew on Andøya during parts of the LGM. The highest relative sea level after the final deglaciation on northern Andøya is bracketed between 36 and 38 m a.s.l. It occurred between 21.0 and 20.3 cal. ka BP, peaking around 20.7 cal. ka BP. The final deglaciation of the northern tip of Andøya occurred 22.2 cal. ka BP. Then the western margin of the Andfjorden ice stream receded to the Kjølhaugen Moraine and shortly thereafter to the Endleten Moraine. Our research confirms that northern Andøya is a key location for understanding the natural environment in northwestern Europe during the LGM.
Insights into the preclinical treatment of blood‐stage malaria by the antibiotic borrelidin
Authors: Azcárate IG , Marín‐García P , Camacho N , Pérez‐Benavente S , Puyet A , Diez A , Ribas de Pouplana L , Bautista JM
Published: March 2013

Background and Purpose

Blood‐stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl‐tRNA synthetases have been validated as antimalarial drug targets. We explored long‐term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria.

Experimental Approach

Long‐term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed.

Key Results

Borrelidin protected against lethal malaria at 0.25 mg·kg−1·day−1. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re‐infection on further challenges, 75 and 340 days after the initial infection. This long‐term immunity in borrelidin‐treated mice resulted in negligible parasitaemia after re‐infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long‐term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts.

Conclusions and Implications

Low borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria.
β1‐Adrenoceptor stimulation suppresses endothelial IKCa‐channel hyperpolarization and associated dilatation in resistance arteries
Authors: Yarova PL , Smirnov SV , Dora KA , Garland CJ
Published: March 2013

Background and Purpose

In small arteries, small conductance Ca2+‐activated K+ channels (SKCa) and intermediate conductance Ca2+‐activated K+ channels (IKCa) restricted to the vascular endothelium generate hyperpolarization that underpins the NO‐ and PGI2‐independent, endothelium‐derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IKCa channels can be negatively regulated by PKA, we investigated whether β‐adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.

Experimental Approach

Rat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca2+]i, mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.

Key Results

Intraluminal perfusion of β‐adrenoceptor agonists inhibited endothelium‐dependent dilatation to ACh (1 nM–10 μM) without modifying the associated changes in endothelial cell [Ca2+]i. The inhibitory effect of β‐adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β‐adrenoceptor antagonists propranolol (non‐selective), atenolol (β1) or the PKA inhibitor KT‐5720, but remained unaffected by ICI 118 551 (β2) or glibenclamide (ATP‐sensitive K+ channels channel blocker). Endothelium‐dependent hyperpolarization to ACh was also inhibited by β‐adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IKCa {with 1 μM 1‐[(2‐chlorophenyl)diphenylmethyl]‐1H‐pyrazole (TRAM‐34)}, but not SKCa (50 nM apamin) channels prevented β‐adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.

Conclusions and Implications

In resistance arteries, endothelial cell β1‐adrenoceptors link to inhibit endothelium‐dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IKCa channels and may be one consequence of raised circulating catecholamines.
Evidence for involvement of central vasopressin V1b and V2 receptors in stress‐induced baroreflex desensitization
Authors: Milutinović‐Smiljanić Sanja , Šarenac Olivera , Lozić‐Djurić Maja , Murphy David , Japundžić‐Žigon Nina
Published: March 2013

Background and Purpose

It is well recognized that vasopressin modulates the neurogenic control of the circulation. Here, we report the central mechanisms by which vasopressin modulates cardiovascular response to stress induced by immobilization.

Experimental Approach

Experiments were performed in conscious male Wistar rats equipped with radiotelemetric device for continuous measurement of haemodynamic parameters: systolic and diastolic BP and heart rate (HR). The functioning of the spontaneous baro‐receptor reflex (BRR) was evaluated using the sequence method and the following parameters were evaluated: BRR sensitivity (BRS) and BRR effectiveness index (BEI).

Key Results

Under baseline physiological conditions intracerebroventricular injection of 100 and 500 ng of selective non‐peptide V1a or V1b or V2 receptor antagonist did not modify BP, HR and BRR. Rats exposed to 15 min long stress by immobilization exhibited increase of BP, HR, reduction of BRS and no change in BEI. Pretreatment of rats with V1a receptor antagonist did not modulate the BP, HR, BRS and BEI response to stress. Pretreatment of rats with V1b receptor and V2 receptor antagonist, at both doses, prevented BRR desensitization and tachycardia, but failed to modulate stress‐induced hypertension.

Conclusions and Implications

Vasopressin by the stimulation of central V1b‐ and V2‐like receptors mediates stress‐induced tachycardia and BRR desensitization. If these mechanisms are involved, BRR desensitization in heart failure and hypertension associated with poor outcome, they could be considered as novel targets for cardiovascular drug development.
Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease
Authors: Doria JG , Silva FR , de Souza JM , Vieira LB , Carvalho TG , Reis HJ , Pereira GS , Dobransky T , Ribeiro FM
Published: March 2013

Background and Purpose

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5‐dependent protective pathways are more activated in HD neurons, intracellular Ca2+ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca2+ release and be neuroprotective in HD.

Experimental Approach

We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca2+ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit.

Key Results

We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca2+ concentration ([Ca2+]i); and Akt blockage leads to loss of PAM‐mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit.

Conclusions and Implications

mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.
Discriminating between 5‐HT3A and 5‐HT3AB receptors
Authors: Thompson AJ , Lummis SCR
Published: March 2013

The 5‐HT3B subunit was first cloned in 1999, and co‐expression with the 5‐HT3A subunit results in heteromeric 5‐HT3AB receptors that are functionally distinct from homomeric 5‐HT3A receptors. The affinities of competitive ligands at the two receptor subtypes are usually similar, but those of non‐competitive antagonists that bind in the pore often differ. A competitive ligand and allosteric modulator that distinguishes 5‐HT3A from 5‐HT3AB receptors has recently been described, and the number of non‐competitive antagonists identified with this ability has increased in recent years. In this review, we discuss the differences between 5‐HT3A and 5‐HT3AB receptors and describe the possible sites of action of compounds that can distinguish between them.
Short‐term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro‐cognitive benefit in a mouse model of Down's syndrome
Authors: Colas D , Chuluun B , Warrier D , Blank M , Wetmore D Z , Buckmaster P , Garner C C , Heller H C
Published: March 2013

Background and Purpose

Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans.

Experimental Approach

Long‐term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short‐term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio‐marker of the treatment.

Key Results

PTZ has a wide therapeutic window (0.03–3 mg·kg−1) that is >10–1000‐fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short‐term, low, chronic dose regimens of pentylenetetrazole elicited long‐lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice.

Conclusions and Implications

Low doses of pentylenetetrazole were safe, produced long‐lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.
Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE)
Authors: Asimakopoulou Antonia , Panopoulos Panagiotis , Chasapis Christos T , Coletta Ciro , Zhou Zongmin , Cirino Giuseppe , Giannis Athanassios , Szabo Csaba , Spyroulias Georgios A , Papapetropoulos Andreas
Published: March 2013

Background and Purpose

Hydrogen sulfide (H2S) is a signalling molecule that belongs to the gasotransmitter family. Two major sources for endogenous enzymatic production of H2S are cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). In the present study, we examined the selectivity of commonly used pharmacological inhibitors of H2S biosynthesis towards CSE and CBS.

Experimental Approach

To address this question, human CSE or CBS enzymes were expressed and purified from Escherichia coli as fusion proteins with GSH‐S‐transferase. After purification, the activity of the recombinant enzymes was tested using the methylene blue method.

Key Results

β‐cyanoalanine (BCA) was more potent in inhibiting CSE than propargylglycine (PAG) (IC50 14 ± 0.2 μM vs. 40 ± 8 μM respectively). Similar to PAG, L‐aminoethoxyvinylglycine (AVG) only inhibited CSE, but did so at much lower concentrations. On the other hand, aminooxyacetic acid (AOAA), a frequently used CBS inhibitor, was more potent in inhibiting CSE compared with BCA and PAG (IC50 1.1 ± 0.1 μM); the IC50 for AOAA for inhibiting CBS was 8.5 ± 0.7 μM. In line with our biochemical observations, relaxation to L‐cysteine was blocked by AOAA in aortic rings that lacked CBS expression. Trifluoroalanine and hydroxylamine, two compounds that have also been used to block H2S biosynthesis, blocked the activity of CBS and CSE. Trifluoroalanine had a fourfold lower IC50 for CBS versus CSE, while hydroxylamine was 60‐fold more selective against CSE.

Conclusions and Implications

In conclusion, although PAG, AVG and BCA exhibit selectivity in inhibiting CSE versus CBS, no selective pharmacological CBS inhibitor is currently available.
HDLand endothelial protection
Authors: Tran‐Dinh A , Diallo D , Delbosc S , Varela‐Perez L Maria , Dang QB , Lapergue B , Burillo E , Michel JB , Levoye A , Martin‐Ventura JL , Meilhac O
Published: March 2013

High‐density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoproteinA‐I(apoA‐I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function,HDLsdisplay pleiotropic effects including antioxidant, anti‐apoptotic, anti‐inflammatory, anti‐thrombotic or anti‐proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark ofHDLaction on endothelial cells. Endothelial cells express receptors for apoA‐IandHDLsthat mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects ofHDLson the endothelium in normal and pathological conditions with a particular focus on the potential use ofHDLtherapy to restore endothelial function and integrity.
Dynamics of giant mass transport in deep submarine environments: the Matakaoa Debris Flow, New Zealand
Authors: Joanne C. , Lamarche G. , Collot J.‐Y.
Published: March 2013

The Matakaoa Debris Flow (MDF) is a 200‐km‐long mass‐transport deposit resulting from the failure of the Matakaoa continental margin, northeast New Zealand, ca. 38–100 ky ago. In this study, high‐quality bathymetric and seismic reflection data are used to identify the morpho‐structural characters that reflect the kinematics of the MDF, as well as its interactions with basin sediments. We demonstrate how the transport energy, together with the local topography led to the present geometry and complex structure of the MDF deposits. The remarkable transport energy of the MDF is demonstrated by its dynamic impact on adjacent sedimentary series, including erosion of the substratum, shearing and compressional deformation. In the proximal zone of transport, momentous substratum erosion, demonstrated by giant tool marks and truncated sediments at the base of the debrite, triggered the excavation of a large volume (>200 km3) of basin sediments. The size of transported blocks (up to 3‐km long) is used to estimate the matrix yield strength in an early stage of transport. In the distal zone of transport, 100 km north of the source, seismic profiles show the propagation of thrust structures from the MDF into adjacent basin sediments. This study highlights that the remarkable volume of 2000 km3 of deposits partly resulted from the propagation of compressive structures within the basin sedimentary series to the front of the debrite.
Can bayesian models play a role in dental caries epidemiology? Evidence from an application to theBELCAPdata set
Authors: Matranga Domenica , Firenze Alberto , Vullo Angela
Published: March 2013

Objectives

The aim of this study was to show the potential ofBayesian analysis in statistical modelling of dental caries data. Because of the bounded nature of the dmft (DMFT) index, zero‐inflated binomial (ZIB) and beta‐binomial (ZIBB) models were considered. The effects of incorporating prior information available about the parameters of models were also shown.

Methods

The data set used in this study was theBeloHorizonteCariesPrevention (BELCAP) study (Böhning et al. (1999)), consisting of five variables collected among 797Brazilian school children designed to evaluate four programmes for reducing caries. Only the eight primary molar teeth were considered in the data set. A data augmentation algorithm was used for estimation. Firstly, noninformative priors were used to express our lack of knowledge about the regression parameters. Secondly, prior information about the probability of being a structural zero dmft and the probability of being caries affected in the subpopulation of susceptible children was incorporated.

Results

With noninformative priors, the best fitting model was theZIBB. Education (OR = 0.76, 95% CrI: 0.59, 0.99), all interventions (OR = 0.46, 95% CrI: 0.35, 0.62), rinsing (OR = 0.61, 95% CrI: 0.47, 0.80) and hygiene (OR = 0.65, 95% CrI: 0.49, 0.86) were demonstrated to be factors protecting children from being caries affected. Being male increased the probability of being caries diseased (OR = 1.19, 95% CrI: 1.01, 1.42). However, after incorporating informative priors,ZIBmodels' estimates were not influenced, whileZIBBmodels reduced deviance and confirmed the association with all interventions and rinsing only.

Discussion

In our application,Bayesian estimates showed a similar accuracy and precision than likelihood‐based estimates, although they offered many computational advantages and the possibility of expressing all forms of uncertainty in terms of probability. The overdispersion parameter could expound why the introduction of prior information had significant effects on the parameters of theZIBBmodel, whileZIBestimates remained unchanged. Finally, the best performance ofZIBBcompared to theZIBmodel was shown to catch overdispersion in data.
Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells
Authors: Tjon A S W , Tha-In T , Metselaar H J , van Gent R , van der Laan L J W , Groothuismink Z M A , te Boekhorst P A W , van Hagen P M , Kwekkeboom J
Published: March 2013

Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4+CD25+forkhead box protein 3 (FoxP3+) Tregs and of conventional CD4+FoxP3− T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs, as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.
The Influence of Platform Switching on Clinical, Laboratory, and Image‐Based Measures: A Prospective Clinical Study
Authors: Dursun Erhan , Tulunoglu Ibrahim , Ozbek S. Murat , Uysal Serdar , Akalın F. Alev , Kilinc Kamer , Karabulut Erdem , Tözüm Tolga F.
Published: March 2013

Purpose

This prospective study was conducted to compare the marginal bone level alterations, stability/mobility measurements, and volume of myeloperoxidase (MPO) and nitric oxide (NO) of peri‐implant sulcus fluid (PISF) between platform‐switched (PS) and standard platform (SP) implants inserted to mandibular premolar/molar regions with a single‐stage protocol.

Materials and Methods

Thirty‐two (16 PS and 16 SP) implants restorated with fixed prosthesis were included in the study. For both implant systems standard implant dimensions were used. Implant abutment connections and final restorations were made after 3 months of osseointegration. Standard parallel periapical radiographs were used to measure marginal bone loss in over time. Resonance frequency analysis (RFA) and mobility measuring (MM) device were used to determine implant stability/mobility. PISF samples were derived with paper strips and PISF MPO and nitrite level analysis were done spectrophotometrically. Peri‐implant parameters were assessed by periodontal indices and all parameters were evaluated at baseline, 1, 3, 6, and 12 months follow‐up.

Results

No healing problems were recorded for all implants at the end of the study period. At 12 months, mean bone loss measures were 0.84 and 0.76 mm, and mean implant stability quotient (ISQ) values were 74.04 and 76 for PS and SP implants, respectively. Mean MM values were found as −4.82 for PS and −6.26 for SP implants. There were no significant differences between implant types according to PISF volume and laboratory biochemical measures including MPO and NO, and clinical peri‐ implant indices at any time point.

Conclusion

Platform switching seems not to affect the marginal bone level, clinical peri‐implant parameters and MPO and NO metabolism around implants inserted to mandibular premolar/molar regions when using a single‐stage protocol.
The Disturbance of Hippocampal CaMKII/PKA/PKC Phosphorylation in Early Experimental Diabetes Mellitus
Authors: Liao Mei‐Hua , Xiang Ying‐Chun , Huang Ji‐Yun , Tao Rong‐Rong , Tian Yun , Ye Wei‐Feng , Zhang Gen‐Sheng , Lu Ying‐Mei , Ahmed Muhammad M. , Liu Zhi‐Rong , Fukunaga Kohji , Han Feng
Published: March 2013

Background

Defining the impact of diabetes and related risk factors on brain cognitive function is critically important for patients with diabetes.

Aims

To investigate the alterations in hippocampal serine/threonine kinases signaling in the early phase of type 1 and type 2 diabetic rats.

Methods

Early experimental diabetes mellitus was induced in rats with streptozotocin or streptozotocin/high fat. Changes in the phosphorylation of proteins were determined by immunoblotting and immunohistochemistry.

Results

Our data showed a pronounced decrease in the phosphorylation of Ca2+/calmodulin‐dependent protein kinase II (CaMKII) in the hippocampi of both type 1 and type 2 diabetic rats compared with age‐matched control rats. Unexpectedly, we found a significant increase in the phosphorylation of synapsin I (Ser 603) and GluR1 (Ser 831) in the same experiment. In addition, aberrant changes in hippocampal protein kinase C (PKC) and protein kinase A (PKA) signaling in type 1 and type 2 diabetic rats were also found. Moreover, PP1α and PP2A protein levels were decreased in the hippocampus of type 1 diabetic rats, but significantly up‐regulated in type 2 diabetic rats.

Conclusions

The disturbance of CaMKII/PKA/PKC phosphorylation in the hippocampus is an early change that may be associated with the development and progression of diabetes‐related cognitive dysfunction.
Prognostic and diagnostic significance of annexin A2 in colorectal cancer
Authors: Yang T. , Peng H. , Wang J. , Yang J. , Nice E. C. , Xie K. , Huang C.
Published: March 2013

Aim

Annexin A2 (ANXA2) is known to be a tumourigenic molecule and is highly expressed in colorectal cancer (CRC). Its diagnostic and prognostic value is not fully understood. This study was designed to investigate the relationship between ANXA2 expression, clinicopathological characteristics, tumour recurrence and survival.

Method

Immunohistochemical staining was used to evaluate ANXA2 expression in 150 matched samples from patients with CRC. Overall survival and recurrence were determined by Kaplan–Meier analysis. The Cox proportional hazards model was used to determine independent factors contributing to survival and recurrence. Receiver operating characteristic (ROC) curve and liner correlation analysis were used to estimate the sensitivity and specificity of ANXA2 expression for clinical diagnosis.

Results

ANXA2 was found to be strongly expressed in poorly differentiated tumours (P < 0.001), late stage (P = 0.020) and lymph node positivity (P = 0.002). ANXA2 expression was significantly related to recurrence (P < 0.001) and survival (P = 0.002). The Cox proportional hazards model indicated that ANXA2 expression [P < 0.001, hazard ratio (HR) = 1.366, 95% CI 1.232–1.515] and tumour location (P = 0.039, HR = 1.891, 95% CI 1.034–3.456) were independent factors in predicting overall survival while ANXA2 expression (P < 0.001, HR = 1.445, 95% CI 1.222–1.709) were independent factors predicting recurrence. Receiver operating characteristic (ROC) (AUC = 0.768, 95% CI = 0.642–0.894) and liner correlation analysis suggested that ANXA2 was suitable for the clinical diagnosis of CRC.

Conclusion

These results indicate that ANXA2 is a biomarker with diagnostic and prognostic potential for patients with CRC.
Towards the harmonization of outcome measures in children with mitochondrial disorders
Authors: Koene Saskia , Jansen Merel , Verhaak Chris M , De Vrueh Remco LA , De Groot Imelda JM , Smeitink Jan AM
Published: March 2013

Aim

A clinical trial is only as reliable as its outcomes, therefore the careful and systematic selection of outcome measures is extremely important. Currently, the selection of outcome measures for clinical trials designed to evaluate new drugs in patients with mitochondrial disorders is inefficient and has not been addressed systematically. Given that meaningful data can be obtained only from trials in which outcomes are assessed using valid instruments, one should first focus on the validation of a set of selected instruments in the target population. The aim of this review is to systematically select a ‘toolbox’ of robust outcome measures that are relevant to all patients.

Method

Using an extensive search of published literature, we systematically compiled a toolbox with outcome measures based on a primary search for possible instruments Subsequently, we reduced this toolbox using strict criteria that were adapted from the United States Food and Drug Administration.

Results

A toolbox with clinically relevant and psychometrically robust instruments for performing clinical research in children with mitochondrial disorders was compiled.

Interpretation

In coming years, more experience using these outcome measures in children with various mitochondrial disease phenotypes must be obtained before reliable conclusions regarding the validity of these instruments can be drawn.
Cardiovascular safety of the dipetidyl peptidase‐4 inhibitor alogliptin in type 2 diabetes mellitus
Authors: White W. B. , Pratley R. , Fleck P. , Munsaka M. , Hisada M. , Wilson C. , Menon V.
Published: March 2013

Aim

As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase‐4 inhibitor alogliptin.

Methods

We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non‐fatal myocardial infarction and non‐fatal stroke.

Results

The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient‐years compared to 691 patients treated with placebo for 263 patient‐years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient‐years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.

Conclusion

These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.
Combination therapy with naltrexone and bupropion for obesity reduces total and visceral adiposity
Authors: Smith S. R. , Fujioka K. , Gupta A. K. , Billes S. K. , Burns C. , Kim D. , Dunayevich E. , Greenway F. L.
Published: March 2013

The effects of combination naltrexone/bupropion therapy on body composition and visceral adipose tissue (VAT) mass were examined in a subset (n = 107) of obese subjects from a Phase 2 trial that compared the efficacy and safety of placebo, naltrexone monotherapy, bupropion monotherapy or one of three naltrexone/bupropion dose combinations for 24 weeks. Body composition data were obtained using dual‐energy X‐ray absorptiometry and computed tomography. Eighty subjects completed the substudy. Naltrexone/bupropion resulted in weight loss and a greater reduction in body fat (−14.0 ± 1.3%) than placebo (−4.0 ± 2.0%), naltrexone monotherapy (−3.2 ± 2.5%) and bupropion monotherapy (−4.1 ± 2.9%; all p < 0.01). Reduction in VAT mass was also greater with naltrexone/bupropion (−15.0 ± 1.8%) than placebo (−4.6 ± 2.7%), naltrexone monotherapy (−0.1 ± 3.5%) and bupropion monotherapy (−2.3 ± 4.2%; all p < 0.01). Reductions in body fat and VAT mass with naltrexone/bupropion were proportional with weight loss. Weight loss with naltrexone/bupropion was not associated with a greater relative reduction in lean mass than placebo or the monotherapies.