bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain penetration and anticonvulsant efficacy of intranasal phenobarbital in rats
Authors: Czapp Marion , Bankstahl Jens P. , Zibell Guido , Potschka Heidrun
Published: March 2008

Summary

Purpose: The use of alternate methods for antiepileptic drug delivery has been proposed as a putative strategy to enhance efficacy and tolerability of chronic pharmacotherapy. Intranasal administration is of specific interest based on its general potential for targeted central nervous system delivery. Therefore we analyzed whether intranasal administration of phenobarbital may render a valuable therapeutic approach.

Methods: Brain penetration of phenobarbital following its intranasal administration in rats was studied by microdialysis and by analysis of brain homogenates. The anticonvulsant efficacy of intranasal phenobarbital was determined in the amygdala kindling model.

Results: Phenobarbital was efficiently delivered to the rat brain following intranasal administration. A mucoadhesive preparation of phenobarbital thereby resulted in brain concentrations that were superior to those obtained with intranasal administration of an aqueous solution. In comparison with concentrations reached following intravenous administration of 5.4 mg/kg phenobarbital, intranasal administration of the same dosage resulted in 2.4‐fold higher Cmax values in cortical dialysates. Ten minutes following intranasal administration, PB concentrations in the olfactory bulb exceeded that in more caudal parts of the brain, thus, indicating that phenobarbital has at least been partially targeted to the brain via local pathways. Testing in the amygdala kindling model demonstrated that effective brain concentrations were reached with intranasal phenobarbital delivery.

Discussion: In conclusion, intranasal administration of phenobarbital in rats is associated with efficient brain penetration rates allowing to achieve therapeutic concentrations. Based on these data, intranasal phenobarbital administration seems to render a suitable alternate delivery route for this antiepileptic drug, which should be further evaluated.
Interictal regional polyspikes in noninvasive EEG suggest cortical dysplasia as etiology of focal epilepsies
Authors: Noachtar Soheyl , Bilgin Özgür , Rémi Jan , Chang Nelly , Midi Ipek , Vollmar Christian , Feddersen Berend
Published: March 2008

Summary

Purpose: To evaluate the clinical significance of interictal regional polyspikes in focal epilepsies secondary to cortical dysplasia.

Methods: We performed a data search for the term “regional polyspikes” in the database of our epilepsy‐monitoring unit. Patients with generalized epilepsies including Lennox‐Gastaut syndrome were excluded. Regional interictal epileptiform discharges were recorded in 513 patients with noninvasive EEG.

Results: We identified 29 patients with interictal regional polyspikes and focal epilepsies. Another 484 patients showed regional epileptiform discharges other than polyspikes. The etiology of the epilepsy was significantly more frequently cortical dysplasia in the group of patients with regional polyspikes (35%, 10 of 29 patients) than in the patients with other regional epileptiform discharges (5%, 24 of 484 patients) (p < 0.01). The polyspikes were significantly more frequently localized to the extratemporal (72%; n = 21) than temporal (28%; n = 8) regions (p < 0.01). In contrast, regional epileptiform discharges other than polyspikes were significantly more frequently localized to the temporal lobe (75%; n = 362) than extratemporal regions (25%; n = 122) (p < 0.01). Eight of the 10 patients with focal cortical dysplasia had extratemporal polyspikes.

Discussion: Noninvasively recorded regional polyspikes suggest cortical dysplasias as etiology of predominantly extratemporal epilepsies.
Cumulative Deficits Better Characterize Susceptibility to Death in Elderly People than Phenotypic Frailty: Lessons from the Cardiovascular Health Study
Authors: Kulminski Alexander M. , Ukraintseva Svetlana V. , Kulminskaya Irina V. , Arbeev Konstantin G. , Land Kenneth , Yashin Anatoli I.
Published: March 2008

OBJECTIVES: To compare how well frailty measures based on a phenotypic frailty approach proposed in the Cardiovascular Health Study (CHS) and a cumulative deficits approach predict mortality.

DESIGN: Cohort study.

SETTING: The main cohort of the CHS.

PARTICIPANTS: Four thousand seven hundred twenty‐one individuals.

MEASUREMENTS: A phenotypic frailty index (PFI) was defined in the same way as proposed in the CHS: assessing weight loss, exhaustion, low physical activity, slowness, and poor grip strength. A cumulative deficit index (DI) was defined based on 48 elderly deficits (signs, symptoms, impairments, diseases) included in the index, with equal weights.

RESULTS: Of the 1,073 frailest individuals with the lowest survival, the PFI, categorized as proposed in the CHS into robust, prefrail, and frail categories, underestimated the risk of death for 720 persons, whereas the DI categorized into the same three frailty categories underestimated the mortality risk for 134 persons. The higher power of the DI for discriminating frail individuals in their susceptibility to death also followed from comparison of quasi‐instantaneous values of both indices. The three‐level DI identified 219 individuals as frail of 361 individuals identified as frail according to the three‐level PFI.

CONCLUSION: The DI can more precisely evaluate chances of death because it assesses a broader spectrum of disorders than the PFI. Both indices appear to be frailty related. Integration of both approaches is highly promising for increasing the precision of discrimination of the risk of death and especially for identification of the most vulnerable elderly people.
Consensus List of Signals to Detect Potential Adverse Drug Reactions in Nursing Homes
Authors: Handler Steven M. , Hanlon Joseph T. , Perera Subashan , Roumani Yazan F. , Nace David A. , Fridsma Douglas B. , Saul Melissa I. , Castle Nicholas G. , Studenski Stephanie A.
Published: March 2008

OBJECTIVES: To develop a consensus list of agreed‐upon laboratory, pharmacy, and Minimum Data Set signals that a computer system can use in the nursing home to detect potential adverse drug reactions (ADRs).

DESIGN: Literature search for potential ADR signals, followed by an internet‐based, a two‐round, modified Delphi survey.

SETTING: A nationally representative survey of experts in geriatrics.

PARTICIPANTS: Panel of 13 physicians, 10 pharmacists, and 13 advanced practitioners.

MEASUREMENTS: Mean score and 95% confidence interval (CI) for each of 80 signals rated on a 5‐point Likert scale (5=strong agreement with likelihood of indicating potential ADRs). Consensus agreement indicated by a lower‐limit 95% CI of 4.0 or greater.

RESULTS: Panelists reached consensus agreement on 40 signals: 15 laboratory and medication combinations, 12 medication concentrations, 10 antidotes, and three Resident Assessment Protocols (RAPs). Highest consensus scores (4.6, 95% CI=4.4–4.9 or 4.4–4.8) were for naloxone when taking opioid analgesics; phytonadione when taking warfarin; dextrose, glucagon, or liquid glucose when taking hypoglycemic agents; medication‐induced hypoglycemia; supratherapeutic international normalized ratio when taking warfarin; and triggering the Falls RAP when taking certain medications.

CONCLUSION: A multidisciplinary expert panel was able to reach consensus agreement on a list of signals to detect potential ADRs in nursing home residents. The results of this study can be used to prioritize an initial list of signals to be included in paper‐ or computer‐based methods for potential ADR detection.
Older Women with Age‐Related Macular Degeneration Have a Greater Risk of Falls: A Physiological Profile Assessment Study
Authors: Szabo Shelagh M. , Janssen Patricia A. , Khan Karim , Potter Michael J. , Lord Stephen R.
Published: March 2008

OBJECTIVES: To determine whether older women with exudative age‐related macular degeneration (AMD) are at greater risk of falls.

DESIGN: Cross‐sectional study.

SETTING: A hospital‐based ophthalmology clinic in Vancouver, Canada.

PARTICIPANTS: One hundred fifteen older (aged ≥70) community‐dwelling women with exudative AMD (AMD cohort) and two control groups: 54 community‐dwelling women without exudative AMD drawn from the same community (non‐AMD cohort) and 341 community‐dwelling Australian women (Australian normative cohort).

MEASUREMENTS: Participants were assessed for falls risk using the short‐form Physiological Profile Assessment (PPA), which provides a fall risk index score and subcomponent measures of vision, proprioception, strength, reaction time, and postural sway.

RESULTS: The mean fall risk index score in the AMD cohort (3.20) was significantly greater than that of the non‐AMD cohort (1.21; P<.001), and fall risk scores increased with age to a greater extent in the AMD cohort. The higher fall risk scores in the AMD cohort resulted from significantly worse performance on each PPA test, not just the test of vision. The AMD cohort also performed worse than the Australian normative cohort in tests of vision, reaction time, and postural sway.

CONCLUSION: Older women with AMD have impaired balance, slow visual reaction times, and poor vision, which in combination result in a significantly greater risk of falls than population norms. These deficits are clearly indicated in the physiological falls profile for the group. Strategies to enhance balance may be particularly beneficial to prevent falls in this group.
Distribution and Correlates of Lipoprotein‐Associated Phospholipase A2 in an Elderly Cohort: The Cardiovascular Health Study
Authors: Furberg Curt D. , Nelson Jeanenne J. , Solomon Cam , Cushman Mary , Jenny Nancy Swords , Psaty Bruce M.
Published: March 2008

OBJECTIVES: To determine whether high levels of lipoprotein‐associated phospholipase A2 (Lp‐PLA2) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp‐PLA2 levels in a community‐based cohort of older adults.

DESIGN: Cross‐sectional.

SETTING: The Cardiovascular Health Study (CHS), a population‐based cohort study of men and women aged 65 and older.

PARTICIPANTS: Five thousand five hundred thirty‐one CHS participants.

MEASUREMENTS: Levels of Lp‐PLA2 activity were determined using stored blood samples from the baseline examination.

RESULTS: Mean Lp‐PLA2 was higher in participants with electrocardiographically determined ventricular conduction defect and major Q‐wave abnormality and was positively correlated with left ventricular (LV) mass. It was high in those with echocardiographically determined abnormal LV ejection fraction, which persisted after adjustment. Mean Lp‐PLA2 was also higher in participants with mild renal insufficiency and kidney disease. After multivariable adjustment, there was a modest but significant 27% greater risk of prevalent CHF per standard deviation increment of Lp‐PLA2 and a modest but significant 12% greater risk of prevalent myocardial infarction. Lp‐PLA2 was weakly but mainly most strongly correlated with cholesterol and lipoproteins, but those correlations were not especially strong. Lp‐PLA2 was weakly positively correlated with soluble intercellular adhesion molecule‐1 but not interleukin‐6. In total, all factors considered could explain only 29% of Lp‐PLA2 activity.

CONCLUSION: Novel findings in the study are the associations, in those aged 65 and older, between Lp‐PLA2 activity and LV dysfunction, CHF, and renal disease. CVD risk factors only minimally explain levels of Lp‐PLA2.
Body Mass Index, Obstructive Sleep Apnea, and Outcomes of Catheter Ablation of Atrial Fibrillation
Authors: JONGNARANGSIN KRIT , CHUGH AMAN , GOOD ERIC , MUKERJI SIDDHARTH , DEY SUJOYA , CRAWFORD THOMAS , SARRAZIN JEAN F. , KUHNE MICHAEL , CHALFOUN NAGIB , WELLS DARRYL , BOONYAPISIT WARANGKNA , PELOSI, Jr FRANK , BOGUN FRANK , MORADY FRED , ORAL HAKAN
Published: March 2008

Background:
Obesity and obstructive sleep apnea (OSA) are associated with atrial fibrillation (AF). The effects of a large body mass index (BMI) and OSA on the results of radiofrequency catheter ablation (RFA) of AF are unclear.

Objective:
To evaluate the effect of BMI and OSA on the efficacy of RFA for AF.

Methods:
RFA was performed in 324 consecutive patients (mean age = 57 ± 11 years) with paroxysmal (234) or chronic (90) AF. OSA was diagnosed by polysomnography in 32 of 324 patients (10%) prior to ablation. Among the 324 patients, 18% had a normal BMI (<25 kg/m2), 39% were overweight (BMI ≥ 25 kg/m2 and <30 kg/m2), and 43% were obese (≥30 kg/m2). RFA was performed to eliminate complex fractionated atrial electrograms (CFAE) in the pulmonary vein antrum and left atrium.

Results:
At 7 ± 4 months after a single ablation procedure, 63% of patients without OSA and 41% with OSA were free from recurrent AF without antiarrhythmic drug therapy (P = 0.02). Multivariate analysis including variables of age, gender, type and duration of AF, OSA, BMI, left atrial size, ejection fraction, and hypertension demonstrated that OSA was the strongest predictor of recurrent AF (OR = 3.04, 95% CI: 1.11–8.32, P = 0.03). There was no association between BMI and freedom from recurrent AF. A serious complication occurred in 3 of 324 patients, with no relationship to BMI.

Conclusions:
OSA is a predictor of recurrent AF after RFA independent of its association with BMI and left atrial size. Obesity does not appear to affect outcomes after radiofrequency catheter ablation of AF.
Ventricular Tachycardia Storm After Initiation of Biventricular Pacing: Incidence, Clinical Characteristics, Management, and Outcome
Authors: NAYAK HEMAL M. , VERDINO RALPH J. , RUSSO ANDREA M. , GERSTENFELD EDWARD P. , HSIA HENRY H. , LIN DAVID , DIXIT SANJAY , COOPER JOSHUA M. , CALLANS DAVID J. , MARCHLINSKI FRANCIS E.
Published: March 2008

Introduction: Cardiac resynchronization therapy (CRT) or biventricular pacing (BVP) is becoming an important treatment option in patients with severe congestive heart failure (CHF) and electrical dyssynchrony. When combined with implantable cardioverter‐defibrillator (ICD) therapy, cardiac resynchronization therapy with a defibrillator (CRT‐D) has been shown to improve quality of life, functional class, and, most recently, survival. However, left ventricular (LV) stimulation in the form of BVP in patients at high risk of developing ventricular tachyarrhythmias has raised concerns that BVP may be proarrhythmic. We describe the incidence, clinical characteristics, and management in a series of patients who developed ventricular tachycardia storm (VTS) after initiation of BVP.

Methods and Results: Clinical data on all patients undergoing CRT‐D were collected prospectively. VTS occurred in eight of 191 (4%) patients and was characterized by recurrent sustained monomorphic ventricular tachycardia (MMVT) with a single morphology. All patients with VTS were men (seven with ischemic heart disease, one with nonischemic cardiomyopathy) with a remote (5 ± 2 years) history of MMVT. VTS developed a mean of 16 ± 12.5 days after initiation of BVP. All patients presented with palpitations and/or decompensated CHF. VTS was refractory to intravenous antiarrhythmic medication and was managed by turning off LV pacing and/or radiofrequency catheter ablation and long‐term oral antiarrhythmic therapy. Despite elimination of VT, presenting with VTS carried a poor prognosis in that all eight patients subsequently developed refractory CHF.

Conclusions: VTS with recurrent MMVT can occur after initiation of BVP. Patients present with decompensated CHF and are best managed by either turning off LV pacing or radiofrequency catheter ablation (RFA) in combination with long‐term antiarrhythmic medication. Despite eliminating MMVT, most patients have poor outcomes.
The Proarrhythmic Effect of Incomplete Pulmotricuspid Isthmus Ablation in a Patient with Sarcoid‐Related Ventricular Tachycardia?
Authors: ARYANA ARASH , D'AVILA ANDRE , RUSKIN JEREMY N. , REDDY VIVEK Y.
Published: March 2008

Proarrhythmia is relatively common after extensive atrial ablation for atrial fibrillation, but has not been frequently documented after catheter ablation of ventricular tachycardia (VT). In theory, this phenomenon could occur if an incomplete ablation line is created between two nonconducting structures, such as dense scar or valvular annuli. This report illustrates the possible proarrhythmic effect of ablation in a patient with sarcoid‐related VT and extensive right ventricular (RV) myopathy who presented with slow incessant VT one month after an ablation procedure including ablation at the pulmotricuspid isthmus (PTI). The extensive preexisting RV myopathy appeared to be an important substrate in the pathogenesis of this patient's incessant VT. This case suggests that the PTI region may serve as a critical tachycardia isthmus if sufficiently modified with an incomplete ablation line in the setting of significant myocardial scarring.
Lone Atrial Fibrillation: Influence of Familial Disease on Gender Predilection
Authors: CHEN LIN Y. , HERRON KATHLEEN J. , TAI BEE C. , OLSON TIMOTHY M.
Published: March 2008

Introduction: Epidemiological studies report a male predominance in lone atrial fibrillation (LAF). Phenotypic differences between sporadic and familial LAF could aid in deciding which cases should undergo family screening. We sought to determine gender distribution in sporadic and familial LAF, gender‐based differences, and phenotypic differences between sporadic and familial LAF.

Methods: Since November 2000, 192 unrelated LAF probands were recruited. Sporadic LAF was defined as the absence of a family history of LAF. Familial LAF was classified as possible if one first‐ or second‐degree relative had LAF, or confirmed if ≥ 2 relatives had LAF. Affected relatives (n = 87) of 34 confirmed familial probands were also evaluated. For unrelated LAF probands, differences in proportions and means were tested using χ2 and ANOVA, respectively. Difference in gender ratio among the family history groups was tested using mixed models.

Results: Male proportion was greater among sporadic (82%) and possible familial probands (84%) than confirmed familial probands (62%), and affected relatives (54%), P < 0.001. Sporadic LAF was more common in men (62%) than women (51%), P = 0.03. More women were affected by palpitation and nocturnal symptoms than men. More patients had permanent AF in the confirmed familial group (27%), compared with the possible familial (7%) and the sporadic LAF group (8%), P = 0.05, but no other phenotypic discriminators were identified.

Conclusions: Male predilection for LAF is attenuated as the likelihood of dominant Mendelian inheritance increases. Increased frequency of “sporadic” LAF among men could be partially due to X‐linked recessive inheritance. Finally, sporadic and familial LAF are clinically indistinguishable.
Accelerated Reactivity Assessment of Light Burnt Magnesium Oxide
Authors: Chau Chung Kong , Li Zongjin
Published: March 2008

Light Burnt magnesium oxide (MgO), also known as magnesia, has a variety of industrial applications, including as the basic ingredient of magnesium oxychloride (MOC) cement. However, it is found that the quality, reactivity in particular, of Light Burnt MgO could vary so much that the workability and performance of magnesia‐based final products can be significantly affected. Consequently, how to measure the reactivity of MgO would be the key for the further development and success of industrial applications of magnesia. To solve the problem, a simple, effective and yet economical test method for evaluating the reactivity of MgO is developed in this study, which utilizes the time required for neutralization to take place between MgO particles and an acidic solution. The experimental results show that the solubility of the major salts produced during the solid‐solution reactions would fundamentally alter the reaction mechanism and thus the speed of the neutralization process. Moreover, the effects of MgO reactivity on the properties of MOC cement are assessed with a series of cement pastes using different MgO batches of various qualities. Finally, a classification of Light Burnt MgO with specific reactivity ranges for different applications is recommended for end users.
Laser Sintering of ZrB2
Authors: Sun Chen‐Nan , Gupta Mool C.
Published: March 2008

Preliminary results about laser sintering of zirconium diboride (ZrB2), a good ultra high‐temperature ceramics candidate, are presented. In order to evaluate a suitable sintering method, single pulsed laser and a concentric dual laser system were carried out. Two different ZrB2 powders having ∼15 and ∼2 μm particle size were assessed for sintering. Scanning electron microscopy images showed that the concentric dual laser sintered layer using ∼2 μm particle size of ZrB2 had relatively smooth surface morphology. X‐ray diffraction results confirmed that the sintered layer mainly retained the crystalline phases as the starting powder. In addition, the rapid cooling rate of laser sintering enabled the formation of needle‐like nanostructures at the sintered surface.
Amber‐colored excreta: a source of arrestment pheromone in firebrats, Thermobia domestica
Authors: Woodbury Nathan , Gries Gerhard
Published: March 2008

Female, male, and juvenile firebrats, Thermobia domestica (Packard) (Thysanura: Lepismatidae), employ a pheromone that arrests conspecifics on contact. Paper shelters placed in a T. domestica colony accumulate fecal excreta (= frass) and other insect‐derived debris. Such shelters elicit arrestment by conspecifics. However, the definitive source of the arrestment pheromone was not known. We tested the hypothesis that one or more debris components from a T. domestica shelter constitute the source of the arrestment pheromone. In dual‐choice, still‐air olfactometer experiments, scales, exuviae, antennae, caudal filaments, gregarine parasite cysts, and silk (each intact or macerated) retrieved from shelters and separated for experiments, as well as saliva, hemolymph, and fat body extracted from insects all failed to arrest female T. domestica. Similarly, paper that had been fed upon by insects did not elicit an arrestment response, eliminating insect‐altered cellulose as the arrestant pheromone. In contrast, insect‐exposed glass significantly arrested females. Moreover, females were significantly arrested by (i) loose, insect‐derived debris brushed from shelters, (ii) a frass mixture manually separated from loose debris, and (iii) specific amber‐type frass manually separated from the frass mixture. These results lead us to conclude that amber‐type frass constitutes the source of at least part of the T. domestica arrestment pheromone.
Relationships between food quality and fitness in the desert locust, Schistocerca gregaria, and its distribution over habitats on the Red Sea coastal plain of Sudan
Authors: Van Huis A. , Woldewahid G. , Toleubayev K. , Van Der Werf W.
Published: March 2008

The effect of millet, Pennisetum typhoideum Rich. (Poaceae), leaf nitrogen content on fitness parameters of the desert locust, Schistocerca gregaria Forsk. (Orthoptera: Acrididae), was studied under laboratory conditions. Locusts reared on high‐nitrogen leaves were larger, developed faster, had higher survival, reproduced more and earlier, and showed greater synchronization than those fed on low‐nitrogen leaves. Active and passive cannibalism contributed to mortality when locusts were reared on low‐nitrogen leaves, but not when reared on high‐nitrogen leaves. Elevated leaf nitrogen content of host plants increased net reproduction and intrinsic rate of increase, and lowered generation time. The findings show that nitrogen content of host plants affects the potential for population increase in the desert locust. Leaf samples of common plant species were collected in the Heliotropium arbainense (Fresen.) (Boraginaceae) and Panicum turgidum (Forssk.) (Poaceae) plant communities on the Red Sea coastal plain of Sudan during the winters of 1999 and 2000. The levels of leaf nitrogen in host plants were comparable to those in the laboratory studies and consistently higher in plant samples from the Heliotropium community than in samples from the Panicum community. Both in 1999 and 2000, locust densities were much higher in the Heliotropium than in the Panicum plant community. It should be assessed whether the desert locust would be attracted to sites where host plants have high leaf nitrogen content, as this would not only increase their fitness, but also the likelihood of gregarization and outbreaks.
Genetic variation in growth and development time under two selection regimes inLeptinotarsa decemlineata
Authors: Lyytinen Anne , Lindström Leena , Mappes Johanna
Published: March 2008

It is possible to predict the potential range of a species on the basis of its ecological characteristics and those of the invaded ecosystem. The existence of genetic variation indicates a species’ potential to respond to new environmental conditions, thus facilitating its success as an invader. Accordingly, evolutionary and ecological approaches are needed to identify the factors explaining both species’ range and their potential to invade new areas. We combined these two approaches and studied whether genetic variation in life‐history traits under abiotic (temperature) and biotic (host plant) selection pressures contributes to the potential range expansion ofLeptinotarsa decemlineataSay (Coleoptera: Chrysomelidae). We reared full‐sib families ofL. decemlineatafrom the current northernmost European population at 15 °C (temperature below that in the current range) and 25 °C (optimal temperature) and on three potato varieties. We monitored development time, adult weight and larval‐to‐adult survival, and estimated the amount of heritable variance. The development time and adult weight of progenies were more variable between than within families. Thus, there was genetic variability in traits relevant to the ability to adapt to a colder environment (i.e., accelerate development and become heavier) allowing range expansion further north in Europe, even though low temperature increased beetle mortality. Temperature strongly affected all traits measured. Potato variety, in turn, did not strongly affect beetles’ performance. Beetle ability to adapt to a cool environment was further enhanced by the fact that size was not constrained by fast development. The results showed that beetle populations possess genetic variation allowing a response to temperature and thus have the evolutionary potential to adapt and spread beyond their current range.
Effect of food deprivation on attractiveness of food sources, containing natural and artificial sugar and protein, to three African fruit flies: Ceratitis cosyra, Ceratitis fasciventris, and Ceratitis capitata
Authors: Manrakhan Aruna , Lux Slawomir Antoni
Published: March 2008

The effects of food deprivation, age, and mating status on the responses of three fruit fly species, Ceratitis cosyra (Walker), Ceratitits fasciventris (Bezzi), and Ceratitits capitata (Wiedemann) (Diptera: Tephritidae) to natural and artificial sugar and protein food sources were investigated. Natural food sources included guava [Psidium guajava L. (Myrtaceae)] juice (a common host fruit for all three fruit fly species) and bird faeces (farm chicken). Artificial food sources included molasses (obtained from a local sugar factory) and a locally produced protein bait (the International Centre of Insect Physiology and Ecology yeast). In all species studied, sugar deprivation of immature (1–2‐day‐old) male and female flies increased their response to food odours, although it did not change their preference for the type of odour (protein or sugar). Protein deprivation of mature (14–17‐day‐old) male and female flies also increased their response to food odours compared to protein‐fed flies. Protein‐deprived females were highly attracted to odours from protein sources in particular. Odours from natural food sources, guava juice, and chicken faeces, were more attractive to food‐deprived flies than were odours from artificial sugar and protein sources. Attraction to food odours increased significantly with increasing age for protein‐deprived females of all species. For males and females of all species, nutritional state was a more important factor than mating status in influencing responses of flies to food odours. Practical implications of these findings are discussed in terms of strategies for fruit fly control using food baits.
Calcium phosphate surfaces promote osteogenic differentiation of mesenchymal stem cells
Authors: Müller Petra , Bulnheim Ulrike , Diener Annette , Lüthen Frank , Teller Marianne , Klinkenberg Ernst‐Dieter , Neumann Hans‐Georg , Nebe Barbara , Liebold Andreas , Steinhoff Gustav , Rychly Joachim
Published: March 2008

Although studies in vivo revealed promising results in bone regeneration after implantation of scaffolds together with osteogenic progenitor cells, basic questions remain how material surfaces control the biology of mesenchymal stem cells (MSC). We used human MSC derived from bone marrow and studied the osteogenic differentiation on calcium phosphate surfaces. In osteogenic differentiation medium MSC differentiated to osteoblasts on hydroxyapatite and BONITmatrix®, a degradable xerogel composite, within 14 days. Cells revealed a higher alkaline phosphatase (ALP) activity and increased RNA expression of collagen I and osteocalcin using real‐time RTPCR compared with cells on tissue culture plastic. To test whether material surface characteristics alone are able to stimulate osteogenic differentiation, MSC were cultured on the materials in expansion medium without soluble additives for osteogenic differentiation. Indeed, cells on calcium phosphate without osteogenic differentiation additives developed to osteoblasts as shown by increased ALP activity and expression of osteogenic genes, which was not the case on tissue culture plastic. Because we reasoned that the stimulating effect on osteogenesis by calcium phosphate surfaces depends on an altered cell–extracellular matrix interaction we studied the dynamic behaviour of focal adhesions using cells transfected with GFP labelled vinculin. On BONITmatrix®, an increased mobility of focal adhesions was observed compared with cells on tissue culture plastic. In conclusion, calcium phosphate surfaces are able to drive MSC to osteoblasts in the absence of osteogenic differentiation supplements in the medium. An altered dynamic behaviour of focal adhesions on calcium phosphate surfaces might be involved in the molecular mechanisms which promote osteogenic differentiation.
Post‐collection,pre‐measurement variables affecting VEGF levels in urine biospecimens
Authors: Hayward Robert M. , Kirk Melissa J. , Sproull Mary , Scott Tamalee , Smith Sharon , Cooley‐Zgela Theresa , Crouse Nancy S. , Citrin Deborah E. , Camphausen Kevin
Published: March 2008

Angiogenesis, the development and recruitment of new blood vessels, plays an important role in tumour growth and metastasis.Vascular endothelial growth factor (VEGF) is an important stimulator of angiogenesis.Circulating and urinary VEGF levels have been suggested as clinically useful predictors of tumour behaviour, and investigations into these associations are ongoing.Despite recent interest in measuring VEGF levels in patients, little is known about the factors that influence VEGF levels in biospecimens. To begin to address this question, urine samples were collected from patients with solid tumours undergoing radiotherapy and healthy volunteers.Four factors were examined for their effects on VEGF concentrations as measured by chemiluminescent immunoassay: time from sample collection to freezing, number of specimen freeze–thaw cycles, specimen storage tube type and the inclusion or exclusion of urinary sediment. The results of this study indicate that time to freeze up to 4 hrs, number of freeze–thaw cycles between one and five, and different types of polypropylene tubes did not have statistically significant effects on measured urinary VEGF levels. Urinary sediment had higher VEGF levels than supernatant in five of six samples from healthy patients.It is not clear whether there is an active agent in the sediment causing this increase or if the sediment particles themselves are affecting the accuracy of the assay.Therefore, we recommend centrifuging urine, isolating the supernatant, and freezing the sample in polypropylene microcentrifuge tubes or cryogenic vials within 4 hrs of collection.In addition, we recommend the use of samples within five freeze–thaw cycles.
Clathrin‐independent internalization and recycling
Authors: Gong Qiang , Huntsman Christopher , Ma Dzwokai
Published: March 2008

Introduction

Clathrin‐dependent internalization

Clathrin‐independent internalization

Macropinocytosis

Caveolae‐dependent internalization

Clathrin‐and‐caveolae‐independent internalization

Pericentrion, a novel PKC‐dependent recycling endosomal structure

Clathrin‐independent pathways in neuronal cells

Summary

The functionality of receptor and channel proteins depends directly upon their expression level on the plasma membrane. Therefore, the ability to selectively adjust the surface level of a particular receptor or channel protein is pivotal to many cellular signalling events. The internalization and recycling pathway plays a major role in the regulation of protein surface level, and thus has been a focus of research for many years. Although several endocytic pathways have been identified, most of our knowledge has come from the clathrin‐dependent pathway, while the other pathways remain much less well defined. Considering that clathrin‐independent internalization may account for as much as 50% of the total endocytic activity in the cell, the lack of such knowledge constitutes a major gap in our efforts to understand how different internalization pathways are utilized and co‐ordinated. Recent studies have provided valuable insights into this area, yet many more questions still remain. In this review, we will give a panoramic introduction to the current knowledge of various internalization and recycling pathways, with an emphasis on the latest findings that have broadened our view of the clathrin‐independent pathways. We will also dedicate one section to the emerging studies of the clathrin‐independent internalization pathways in neuronal cells.
Mef2c is an essential regulatory element required for unique expression of the cardiac‐specific CARK gene
Authors: Wang Hu , Chen Chen , Song Xiaodong , Chen Jingzhou , Zhen Yisong , Sun Kai , Hui Rutai
Published: March 2008

The cardiac ankyrin repeat kinase (CARK) gene, also named TNNI3K for its interaction with cardiac troponin I, is both a unique expression and heart‐enriched gene. To understand the mechanisms of CARK gene expression and regulation, we first cloned the full‐length mRNA sequence and mapped the transcription start site of the mouse CARK gene and characterized its promoter regions. Two transcriptional isoforms of the CARK gene were identified in mouse heart tissue. Truncation analysis of the CARK promoter identified a minimal 151 bp region that has strong basal transcription activity. Mutational analysis revealed five conserved cis‐acting elements in this 151‐bp long minimal promoter. Mutational and loss‐of‐functional analysis and co‐transfection studies indicated that MEF2 binding region is the most critical cis‐acting element in the CARK promoter, and CARK transcription level can be down‐regulated by MEF2C antisense. Binding to the MEF2 sites by Mef2c protein was confirmed by electrophoretic mobility shift assay and competition and supershift electrophoretic mobility shift assays.
Protein prenylation in glucose‐induced insulin secretion from the pancreatic islet β cell: a perspective
Authors: Kowluru Anjaneyulu
Published: March 2008

Insulin secretion – a simplified view

Endogenous GTP and its binding proteins are important for GSIS

G‐proteins undergo post‐translational modifications

Data accrued from studies involving generic inhibitors of protein prenylation

Data accrued from studies involving site‐specific inhibitors of protein prenylation

Data accrued from studies involving over‐expression of inactive mutants of PPTases

What are the functional consequences of prenylation in the islet β cell?

How are PPTases regulated by glucose in the islet?

Conclusions and future directions

Insulin secretion from the pancreatic β cell is regulated principally by the ambient concentration of glucose. However, the molecular and cellular mechanisms underlying the stimulus – secretion coupling of glucose‐stimulated insulin secretion (GSIS) remain only partially understood. Emerging evidence from multiple laboratories suggests key regulatory roles for GTP‐binding proteins in the cascade of events leading to GSIS. This class of signalling proteins undergoes a series of requisite post‐translational modifications (e.g. prenylation) at their C‐terminal cysteines, which appear to be necessary for their targeting to respective membranous sites for optimal interaction with their respective effector proteins. This communication represents a perspective on potential regulatory roles for protein prenylation steps (i.e. protein farnesylation and protein geranylgeranylation) in GSIS from the islet β cell.Possible consequences of protein prenylation and potential mechanisms underlying glucose‐induced regulation of prenylation, specifically in the context of GSIS, are also discussed.
Pleomorphism of the nuclear envelope in breast cancer: a new approach to an old problem
Authors: Bussolati Gianni , Marchiò Caterina , Gaetano Laura , Lupo Rosanna , Sapino Anna
Published: March 2008

In routine practice, nuclear pleomorphism of tumours is assessed by haematoxylin staining of the membrane‐bound heterochromatin. However, decoration of the nuclear envelope (NE) through the immunofluorescence staining of NE proteins such as lamin B and emerin can provide a more objective appreciation of the nuclear shape. In breast cancer, nuclear pleomorphism is one of the least reproducible parameters to score histological grade, thus we sought to use NE proteins to improve the reproducibility of nuclear grading. First, immuno‐fluorescence staining of NE as well as confocal microscopy and three‐dimensional reconstruction of nuclei in cultured cells showed a smooth and uniform NE of normal breast epithelium in contrast to an irregular foldings of the membrane and the presence of deep invaginations leading to the formation of an intranuclear scaffold of NE‐bound tubules in breast cancer cells. Following the above methods and criteria, we recorded the degree of NE pleomorphism (NEP) in a series of 273 invasive breast cancers tested by immunofluorescence. A uniform nuclear shape with few irregularities (low NEP) was observed in 135 cases or, alternatively, marked folds of the NE and an intranuclear tubular scaffold (high NEP cases) were observed in 138 cases. The latter features were significantly correlated (P‐value <0.002) with lymph node metastases in 54 histological grade 1 and in 173 cancers with low mitotic count. Decoration of the NE might thus be regarded as a novel diagnostic parameter to define the grade of malignancy, which parallels and enhances that provided by routine histological procedures.
The glucocorticoid receptor signalling in breast cancer
Authors: Moutsatsou Paraskevi , Papavassiliou Athanasios G.
Published: March 2008

Introduction

Concluding remarks

Glucocorticoids (GCs) are provided as co‐medication with chemotherapy in breast cancer, albeit several lines of evidence indicate that their use may have diverse effects and in fact may inhibit chemosensitivity. The molecular basis of GC‐induced resistance to chemotherapy in breast cancer remains poorly defined. Recent researchers, in an attempt to clarify some aspects of the underlying pathways, provide convincing evidence that GCs induce effects that are dependent upon the glucocorticoid‐receptor (GR)‐mediated transcriptional regulation of specific genes known to play key roles in cellular/tissue functions, including growth, apoptosis, differentiation, metastasis and cell survival. In this review, we focus on how GC‐induced chemoresistance in breast cancer is mediated by the GR, unravelling the molecular interplay of GR signalling with other signalling cascades prevalent in breast cancer. We also include a detailed description of GR structure and function, summarizing data gained during recent years into the mechanism(s) of the cross‐talk between the GR and other signalling cascades and secondary messengers, via which GCs exert their pleiotropic effects.
Expression of the NF‐κB inhibitor ABIN‐3 in response to TNF and toll‐like receptor 4 stimulation is itself regulated by NF‐κB
Authors: Verstrepen Lynn , Adib‐Conquy Minou , Kreike Marja , Carpentier Isabelle , Adrie Christophe , Cavaillon Jean‐Marc , Beyaert Rudi
Published: March 2008

Although the nuclear factor‐κB (NF‐κB)‐dependent gene expression is critical to the induction of an efficient immune response to infection or tissue injury, excessive or prolonged NF‐κB signalling can contribute to the development of several inflammatory diseases. Therefore, the NF‐κB signal transduction pathway is tightly regulated by several intracellular proteins. We have previously identified A20‐binding inhibitor of NF‐κB activation (ABIN)‐3 as an lipopolysaccharide (LPS)‐inducible protein in monocytes that negatively regulates NF‐B activation in response to tumour necrosis factor (TNF) and LPS. Here we report that ABIN‐3 expression is also up‐regulated upon TNF treatment of monocytes and other non‐myeloid cell types. We also found a significantly enhanced expression of ABIN‐3 in monocytes of sepsis patients, which is restored to control levels by corticotherapy. To further understand the transcriptional regulation of ABIN‐3 expression, we isolated the human ABIN‐3 promoter and investigated its activation in response to TNF and LPS. This revealed that the LPS‐ and TNF‐inducible expression of ABIN‐3 is dependent on the binding of NF‐κB to a specific B site in the ABIN‐3 promoter. Altogether, these data indicate an important role for NF‐κB‐dependent gene expression of ABIN‐3 in the negative feedback regulation of TNF receptor and toll‐like receptor 4 induced NF‐κB activation.
Intravital multi‐photon microscopy reveals several levels of heterogeneity in endocytic uptake by mouse renal proximal tubules
Authors: Caplanusi A. , Parreira K.S. , Lima W. Rezende , Marien B. , Van Der Smissen P. , De Diesbach P. , Devuyst O. , Courtoy P.J.
Published: March 2008

Understanding renal function requires one to integrate the structural complexity of kidney nephrons and the dynamic nature of their cellular processes. Multi‐photon fluorescence microscopy is a state‐of‐the‐art imaging technique for in vivo analysis of kidney tubules structure and function in real time. This study presents visual evidence for several levels of heterogeneity of proximal tubular endocytic uptake in the superficial renal mouse cortex and illustrates the potential of multi‐photon microscopy for providing a comprehensive and dynamic portrayal of renal function.
microRNAs: a new emerging class of players for disease diagnostics and gene therapy
Authors: Zhang Baohong , Farwell M. A.
Published: March 2008

Introduction

Roles of miRNAs in human disease and miRNAs as a novel biomarker for cancer and disease diagnostics

miRNAs as new targets for gene therapy

Concluding remarks and future perspectives

microRNAs (miRNAs) are a new class of non‐protein‐coding small RNAs, which regulate the expression of more than 30% protein‐coding genes. The unique expression profiles of different miRNAs in different types of cancers and at different stages in one cancer type suggest that miRNAs can function as novel biomarkers for disease diagnostics and may present a new strategy for miRNA gene therapy. Anti‐miRNAs and antisense oligonucleotides (ASO) have been employed to inhibit specific miRNA expression in vitro and in vivo for investigational and clinical purposes. Although miRNA‐based diagnostics and gene therapy are still in their infancy, their huge potentials will meet our need for future disease diagnostics and gene therapy. High efficient delivery of miRNAs into targeted sites, designing accurate anti‐miRNA/ASOs, and related biosafety issues are three major challenges in this field.
The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine
Authors: Eyden B.
Published: March 2008

Introduction

The evolving definition of the myofibroblast: promoting an understanding of biology and pathology

The myofibroblast in fibrotic conditions, tumour stroma and tissue engineering – a therapeutic target in translational medicine

Conclusions

The phrase ‘translational research’conveys the idea of the pursuit of applications for the treatment of human disease.The myofibroblast, long known for having a role in wound‐healing, and for its presence in fibrotic conditions and tumour stroma, is becoming a focus for translational research, not least through its increasingly documented role as a tumour‐promoting cell.In fibroproliferative conditions, cancer and tissue engineering, the myofibroblast, derived partly and possibly from circulating bone‐marrow‐derived cells and epithelial‐to‐mesenchymal transformation, is attracting great attention.In cancer, this cell was initially regarded as a barrier to tumour dissemination, but there is now a growing body of evidence to indicate that it is an active participant in tumour progression.While the involvement of the myofibroblast in these pathological processes is pushing the myofibroblast into the limelight of translational medicine as a target for potential anti‐fibrotic and anti‐cancer therapy, there are still numerous indications from the literature that the myofibroblast is a poorly understood cell in terms of its differentiation.Partly, this is due to a failure to appreciate the contribution of electron microscopy to understanding the nature of this cell.This paper, therefore, is devoted to detailing the principal phenotypic characteristics of the myofibroblast and promotes the argument that understanding how the myofibroblast carries out its roles in normal biological and in pathological processes will be enhanced by a sound understanding of its cellular differentiation, which in turn arguably demands a significant ultrastructural input.
Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome
Authors: Jones L. C. , Earley C. J. , Allen R. P. , Jones B. C.
Published: March 2008

The gene, BTBD9, was recently linked to restless legs syndrome, periodic limb movements and iron status in humans. In a homologous region in mouse, an area containing btbd9 was also identified as being related to iron homeostasis. This finding is important as iron status in brain has been implicated in restless legs syndrome.
Predator stress induces behavioral inhibition and amygdala somatostatin receptor 2 gene expression
Authors: Nanda S. A. , Qi C. , Roseboom P. H. , Kalin N. H.
Published: March 2008

Psychological stressors precipitate and maintain stress‐induced psychopathology, and it is likely that altered amygdala function underlies some of the deleterious effects of psychological stress. To understand the mechanisms underlying the linkage between the response to psychological stressors and maladaptive or psychopathological responses, we have focused on amygdala responsivity in animal models employing species‐specific psychological stressors. In the present study, we characterized the effects of a 15‐min exposure to a natural predator, the ferret, on rat behavior and the expression of the somatostatin family of genes in the amygdala. We examined the somatostatin family of genes because substantial evidence shows that central somatostatin systems are altered in various neuropsychiatric illnesses. We report that rats respond to acute ferret exposure with a significant increase in fearful and anxious behaviors that is accompanied by robust amygdala activation and an increase in somatostatin receptor 2 (sst2) messenger RNA expression within the amygdala and anterior cingulate cortex. These studies are the first to show stress‐induced changes in amygdala sst2 expression and may represent one mechanism by which psychological stress is linked to adaptive and maladaptive behavioral responses.