bluuebunny/crossref_metadata_2025 huggingface dataset:
Signaling Quality Through Specialization
Authors: Kalra Ajay , Li Shibo
Published: April 2008

Firms frequently position themselves as specialists. An implication of specialization is that the firm has forgone alternative opportunities. In the context of effort-intensive categories, we show that a firm can signal quality to consumers by specializing. In the model, a firm must decide to provide one service offering or to market two services. By entering a single category, the firm incurs an opportunity cost of not entering the secondary profitable category, but may attain reduced costs. The net cost is the signaling cost that a high-quality type firm incurs to signal quality over a low-quality type firm. We show that in homogenous markets, a high-quality type firm signals its high-quality type by specializing in one category. When consumers are heterogeneous, the firm can signal its high-quality type by using prices alone in both the primary and secondary categories. However, specialization can be used as a secondary signal of quality in heterogeneous markets because of lower signaling costs. We also find that signaling using specialization is more likely in the presence of competition.
The Invariant Proportion of Substitution Property (IPS) of Discrete-Choice Models
Authors: Steenburgh Thomas J.
Published: April 2008

This article introduces a newly discovered property of discrete-choice models, which I call the invariant proportion of substitution (IPS). Like the independence from irrelevant alternatives (IIA) property, IPS implies individual behavior that is counterintuitive in the context of choice among similar alternatives. But models that alleviate the concerns raised by IIA, such as generalized extreme value and covariance probit models, do not necessarily alleviate the concerns raised by IPS. I explore the implications of the IPS property on individual behavior in several choice contexts and discuss some models that alleviate the concerns raised by IPS.
Consumer Privacy and Marketing Avoidance: A Static Model
Authors: Hann Il-Horn , Hui Kai-Lung , Lee Sang-Yong T. , Png Ivan P. L.
Published: April 2008

We introduce the concept of marketing avoidance—consumer efforts to conceal themselves and to deflect marketing. The setting is one in which sellers market some item through solicitations to potential consumers, who differ in their benefit from the item and suffer harm from receiving solicitations. Concealment by one consumer induces sellers to shift solicitations to other consumers, whereas deflection does not. Solicitations cause two externalities: direct harm on consumers and the (indirect) cost of consumer concealment and deflection. We find that in markets where the marginal cost of solicitation is sufficiently low, efforts by low-benefit consumers to conceal themselves will increase the cost-effectiveness of solicitations and lead sellers to market more. However, concealment by high-benefit consumers leads sellers to market less. Furthermore, concealment by low-benefit consumers increases direct privacy harm, and consumer welfare is higher with deflection than concealment. Finally, it is optimal to impose a charge on solicitations.
Rifamycin Antibiotics for Treatment of Clostridium difficile–Associated Diarrhea
Authors: Garey Kevin W , Salazar Miguel , Shah Dhara , Rodrigue Richard , DuPont Herbert L
Published: April 2008

Objective:

To review the existing data on use of the rifamycin class of antibiotics as therapy for Clostridium difficile–associated diarrhea (CDAD).

Data Sources:

A literature search was performed using PubMed (1996–January 2008), abstracts from the International Conference on Antimicrobial Agents and Chemotherapy (September 2007), the Infectious Diseases Society of America (October 2007), Salix Pharmaceuticals Web site (January 2008), ActivBiotics Web site (January 2008). Google Scholar, and searches of selected bibliographies using the terms rifamycin, ansamycins, rifampin, rifabutin, rifampicin, rifaximin, rifalazil, Clostridium difficile, C. difficile, and CDAD.

Study Selection and Data Extraction:

In vivo and in vitro studies investigating the use of rifamycins for CDAD were selected, along with all clinical trials using rifamycins in patients with CDAD.

Data Synthesis:

Nine studies totaling 890 isolates were identified that investigated the in vitro susceptibility of rifampin (6 studies), rifaximin (3 studies), and rifalazil (2 studies). Rifamycins consistently displayed potent activity against tested strains, although strains with decreased susceptibility have been identified. Six published clinical studies involving 81 patients have investigated the use of rifamycins for the treatment of CDAD. These have generally been small studies, although initial positive clinical results have been reported on the use of rifamycins for recurrent CDAD.

Conclusions:

Preliminary data support the use of rifamycins for treatment of CDAD. With the increased incidence and severity of CDAD, further investigation into this drug class as a treatment regimen for CDAD is warranted.
Roles of Calcium-Stimulated Adenylyl Cyclase and Calmodulin-Dependent Protein Kinase IV in the Regulation of FMRP by Group I Metabotropic Glutamate Receptors
Authors: Wang Hansen , Wu Long-Jun , Zhang Fuxing , Zhuo Min
Published: April 2008

The fragile X syndrome is caused by the lack of fragile X mental retardation protein (FMRP) attributable to silencing of theFMR1gene. The metabotropic glutamate receptors (mGluRs) in the CNS contribute to different brain functions, including learning/memory, mental disorders, drug addiction, and persistent pain. Most of the previous studies have been focused on downstream targets of FMRP in hippocampal neurons, and fewer studies have been reported for the second-messenger signaling pathways between group I mGluRs and FMRP. Furthermore, no molecular study has been performed in the anterior cingulate cortex (ACC), a key region involved in high brain cognitive and executive functions. In this study, we demonstrate that activation of group I mGluR upregulated FMRP in ACC neurons of adult mice through the Ca2+-dependent signaling pathways. Using genetic approaches, we found that Ca2+/calmodulin-stimulated adenylyl cyclase 1 (AC1) and calcium/calmodulin-dependent kinase IV (CaMKIV) contribute to the upregulation of FMRP induced by stimulating group I mGluRs. The upregulation of FMRP occurs at the transcriptional level. The cAMP-dependent protein kinase is activated by stimulating group I mGluRs through AC1 in ACC neurons. Both AC1 and CaMKIV contribute to the regulation of FMRP by group I mGluRs probably through cAMP response element-binding protein activation. Our study has provided the first evidence for a molecular link between group I mGluRs and FMRP in ACC neurons and may help us to understand the pathogenesis of fragile X syndrome.
Learning Stochastic Reward Distributions in a Speeded Pointing Task
Authors: Seydell Anna , McCann Brian C. , Trommershäuser Julia , Knill David C.
Published: April 2008

Recent studies have shown that humans effectively take into account task variance caused by intrinsic motor noise when planning fast hand movements. However, previous evidence suggests that humans have greater difficulty accounting for arbitrary forms of stochasticity in their environment, both in economic decision making and sensorimotor tasks. We hypothesized that humans can learn to optimize movement strategies when environmental randomness can be experienced and thus implicitly learned over several trials, especially if it mimics the kinds of randomness for which subjects might have generative models. We tested the hypothesis using a task in which subjects had to rapidly point at a target region partly covered by three stochastic penalty regions introduced as “defenders.” At movement completion, each defender jumped to a new position drawn randomly from fixed probability distributions. Subjects earned points when they hit the target, unblocked by a defender, and lost points otherwise. Results indicate that after ∼600 trials, subjects approached optimal behavior. We further tested whether subjects simply learned a set of stimulus-contingent motor plans or the statistics of defenders' movements by training subjects with one penalty distribution and then testing them on a new penalty distribution. Subjects immediately changed their strategy to achieve the same average reward as subjects who had trained with the second penalty distribution. These results indicate that subjects learned the parameters of the defenders' jump distributions and used this knowledge to optimally plan their hand movements under conditions involving stochastic rewards and penalties.
A Destructive Interaction Mechanism Accounts for Dominant-Negative Effects of Misfolded Mutants of Voltage-Gated Calcium Channels
Authors: Mezghrani Alexandre , Monteil Arnaud , Watschinger Katrin , Sinnegger-Brauns Martina J. , Barrère Christian , Bourinet Emmanuel , Nargeot Joël , Striessnig Jörg , Lory Philippe
Published: April 2008

Channelopathies are often linked to defective protein folding and trafficking. Among them, the calcium channelopathy episodic ataxia type-2 (EA2) is an autosomal dominant disorder related to mutations in the pore-forming Cav2.1 subunit of P/Q-type calcium channels. Although EA2 is linked to loss of Cav2.1 channel activity, the molecular mechanism underlying dominant inheritance remains unclear. Here, we show that EA2 mutants as well as a truncated form (DI-II) of the Cav3.2 subunit of T-type calcium channel are misfolded, retained in the endoplasmic reticulum, and subject to proteasomal degradation. Pulse-chase experiments revealed that misfolded mutants bind to nascent wild-type Cavsubunits and induce their subsequent degradation, thereby abolishing channel activity. We conclude that this destructive interaction mechanism promoted by Cavmutants is likely to occur in EA2 and in other inherited dominant channelopathies.
Dynamics of Somatostatin Type 2A Receptor Cargoes in Living Hippocampal Neurons
Authors: Lelouvier Benjamin , Tamagno Gianluca , Kaindl Angela M. , Roland Alexandre , Lelievre Vincent , Le Verche Virginia , Loudes Catherine , Gressens Pierre , Faivre-Baumann Annie , Lenkei Zsolt , Dournaud Pascal
Published: April 2008

Despite the large number of G-protein-coupled receptor (GPCR) types expressed in the CNS, little is known about their dynamics in neuronal cells. Dynamic properties of the somatostatin type 2A receptor were therefore examined in resting conditions and after agonist activation in living hippocampal neurons. Using fluorescence recovery after photobleaching experiments, we found that, in absence of ligand, the sst2Areceptor is mobile and laterally and rapidly diffuse in neuronal membranes. We then observed by live-cell imaging that, after agonist activation, membrane-associated receptors induce the recruitment of β-arrestin 1–enhanced green fluorescent protein (EGFP) and β-arrestin 2-EGFP to the plasma membrane. In addition, β-arrestin 1-EGFP translocate to the nucleus, suggesting that this protein could serve as a nuclear messenger for the sst2Areceptor in neurons. Receptors are then recruited to preexisting clathrin coated pits, form clusters that internalize, fuse, and move to a perinuclear compartment that we identified as thetrans-Golgi network (TGN), and recycle. Receptor cargoes are transported through a microtubule-dependent process directly from early endosomes/recycling endosomes to the TGN, bypassing the late endosomal compartment. Together, these results provide a comprehensive description of GPCR trafficking in living neurons and provide compelling evidence that GPCR cargoes can recycle through the TGN after endocytosis, a phenomenon that has not been anticipated from studies of non-neuronal cells.
Multiple Modes of Network Homeostasis in Visual Cortical Layer 2/3
Authors: Maffei Arianna , Turrigiano Gina G.
Published: April 2008

Sensory experience is crucial for shaping the cortical microcircuit during development and is thought to modify network function through several forms of Hebbian and homeostatic plasticity. Where and when these different forms of plasticity are expressed at particular synapse types within cortical microcircuits, and how they interact, is poorly understood. Here we investigated how two different visual deprivation paradigms, lid suture (LS) and intraocular TTX, affect the local microcircuit within layer 2/3 of rat visual cortex during the classical critical period for visual system plasticity. Both forms of visual deprivation produced a compensatory increase in the spontaneous firing of layer 2/3 pyramidal neurons in acute slices derived from monocular visual cortex. TTX increased spontaneous activity through an increase in the excitation/inhibition (E/I) balance within layer 2/3. In contrast, LS decreased the E/I balance by strongly depressing excitatory transmission, and the homeostatic increase in spontaneous activity was instead achieved through an increase in the intrinsic excitability of layer 2/3 pyramidal neurons. The microcircuit in layer 2/3 can thus use different forms of homeostatic plasticity to compensate for the loss of visual drive, depending on the specific demands produced by visual experience. The existence of multiple, partially redundant forms of homeostatic plasticity may ensure that network compensation can be achieved in response to a wide range of sensory perturbations.
Sex-Specific Differences in Expression of Histone DemethylasesUtxandUtyin Mouse Brain and Neurons
Authors: Xu Jun , Deng Xinxian , Watkins Rebecca , Disteche Christine M.
Published: April 2008

Although X inactivation is thought to balance gene expression between the sexes, some genes escape inactivation, potentially contributing to differences between males and females.Utx(ubiquitously transcribed tetratricopeptide repeat gene on X chromosome) is an escapee gene that encodes a demethylase specific for lysine 27 of histone H3, a mark of repressed chromatin. We foundUtxto be expressed higher in females than in males in developing and adult brains and in adult liver. XX mice had a higher level ofUtxthan XY mice, regardless of whether they had testes or ovaries, indicating that the sexually dimorphic gene expression was a consequence of the sex chromosome complement. Females had significantly higher levels ofUtxthan males in most brain regions except in the amygdala. The regional expression of the Y-linked paralogueUty(ubiquitously transcribed tetratricopeptide repeat gene on Y chromosome) was somewhat distinct from that ofUtx, specifically in the paraventricular nucleus of the hypothalamus (highUty) and the amygdala (highUtx), implying that the two paralogues may be differentially regulated. Higher expression ofUtxcompared withUtywas detected in P19 pluripotent embryonic carcinoma cells as well as in P19-derived neurons. This transcriptional divergence between the two paralogues was associated with high levels of histone H3 lysine 4 dimethylation at theUtxpromoter and of histone H4 lysine 16 acetylation throughout the gene body, which suggests that epigenetic mechanisms control differential expression of paralogous genes.
Neuronal Bases of Directional Expectation and Anticipatory Pursuit
Authors: de Hemptinne Coralie , Lefèvre Philippe , Missal Marcus
Published: April 2008

Expectation of upcoming events is an essential cognitive function on which anticipatory actions are based. The neuronal basis of this prospective representation is poorly understood. We trained rhesus monkeys in a smooth-pursuit task in which the direction of upcoming target motion was indicated using a color cue. Under these conditions, directional expectation frequently evoked anticipatory smooth movements. We found that the activity of a population of neurons in the supplementary eye fields encoded the expected future direction of the target. Neuronal activity increased after presentation of the cue, indicating future target motion in the preferred direction. Neuronal activity either remained unaltered or was reduced if the antipreferred direction was cued. In addition, ∼30% of these neurons were more active during trials with anticipatory pursuit in the preferred direction than during trials when monkeys did not anticipate target motion onset. This subset of recorded neurons encoded the direction of the subsequent anticipatory pursuit. We hypothesize that the neural representation of directional expectation could be conceptualized as a competitive interaction between pools of neurons representing likely future events, with the winner of this competition determining the direction of the subsequent anticipatory movement. Similar mechanisms could drive prediction before movement initiation in other motor domains.
Preparing to Move Increases the Sensitivity of Superior Colliculus Neurons
Authors: Li Xiaobing , Basso Michele A.
Published: April 2008

How the brain selects goals for movements remains unknown. The system designed to move the eyes rapidly, the saccadic system, may play a role. Here we ask how sensory signals within a saccade area are influenced by selecting and preparing a saccade. Trained monkeys made or withheld saccades, based on a color cue, to targets varying in luminance contrast. We measured the initial visual activity of superior colliculus (SC) neurons in response to the appearance of these targets. We determined neuronal contrast responses in three task conditions: when two luminance gratings appeared one in the response field (RF) and one in the mirror-opposite location and a cue to select the stimulus in the RF occurred; when the gratings appeared and a cue to select the stimulus out of the RF occurred; and third, when the gratings appeared but monkeys remained fixating on the central spot. SC neurons had increases in visual responses when contrast increased. Receiver operating characteristic analysis revealed an increased ability of neurons to detect the grating on trials with higher contrast targets and also on trials with a cue to make a saccade compared with trials with a cue to remain fixating. Using two measures of neuronal sensitivity, those SC neurons considered part of the motor circuitry increased their sensitivity to contrast with a cue to make a saccade. The results indicate that movement commands influence sensory responses in SC in much the same way that commands to shift attention influence sensory responses in extrastriate cortex.
Nonurological uses of botulinum toxin in gynaecology
Authors: Anbazhagan Akila , Roberts Ralph
Published: April 2008

Botulinum toxin is a powerful neurotoxin which causes temporary flaccid muscle paralysis.

A number of potential gynaecological applications have been described in addition to the well‐established uses in urogynaecology.

Learning objectives:

To understand how botulinum toxin works.

To learn about the preparations available and their contraindications and side‐effects.

To be aware of the potential uses of botulinum toxin in the treatment of vaginismus and other gynaecological pain syndromes.

Ethical issues:

Many of the uses described are still essentially experimental, although largely accepted into mainstream practice: does this need to be acknowledged when counselling women?

Please cite this article as: Anbazhagan A, Roberts R. Nonurological uses of botulinum toxin in gynaecology. The Obstetrician & Gynaecologist 2008;10:75–79.
Preimplantation testing for chromosome aneuploidy
Authors: Ogilvie Caroline Mackie
Published: April 2008

Around 50% of cleavage stage human embryos obtained by in vitro fertilisation (IVF) have an abnormal number of chromosomes.

Aneuploidy testing has been introduced at some IVF centres with the aim of identifying and removing abnormal embryos and increasing pregnancy success rates.

Randomised controlled trials have indicated that pregnancy and live birth rates are lower for women undergoing aneuploidy testing.

Learning objectives:

To understand the nature and frequency of chromosome abnormalities in cleavage stage human embryos.

To understand the rationale underlying aneuploidy testing.

To understand the results of research on aneuploidy testing.

Ethical issues:

Should aneuploidy testing be offered, when randomised trials indicate either that it has no effect or that it results in fewer ongoing pregnancies and live births?

Please cite this article as: Ogilvie CM. Preimplantation testing for chromosome aneuploidy. The Obstetrician & Gynaecologist 2008;10:88–92.
Putting the principles of good governance into clinical practice
Authors: Churchill David
Published: April 2008

An understanding of the principles of good governance will enable doctors to construct more effective and robust departments.

Healthcare organisations are best suited to a task culture where expert power and team working are respected.

A holistic approach should be applied to governing a department.

Monitoring the effectiveness of a department is crucial.

Learning objectives:

How to apply the principles of governance to departmental structures.

How organisational culture can influence the effectiveness of an organisation

Ethical issues:

Has the bureaucracy surrounding clinical governance diverted attention away from its real intent of improving quality of care?

Please cite this article as: Churchill D. Putting the principles of good governance into clinical practice. The Obstetrician & Gynaecologist 2008;10:93–98.
A view on why immediate cord clamping must cease in routine obstetric delivery
Authors: Hutchon David
Published: April 2008

There is good evidence that immediate cord clamping can harm the newborn baby.

Delaying cord clamping for at least 30 seconds is possible in all deliveries.

Learning objectives:

To increase awareness of the need for routine delayed clamping by obstetricians and midwives.

To explore the practice in the presence of fetal distress and nuchal cord.

Ethical issues:

How can a balance be struck between the legal drive for cord blood measurements at birth, which requires immediate cord clamping, and the therapeutically driven delay in cord clamping?

Please cite this article as: Hutchon D. A view on why immediate cord clamping must cease in routine obstetric delivery. The Obstetrician & Gynaecologist 2008;10:112–116.
SARC-CTOS Imaging Symposium: Introduction to the Problem from a Clinical Perspective
Authors: Benjamin Robert S.
Published: April 2008

Failure to correctly design clinical trials precludes effective evaluation of yield data. For instance, the Response Evaluation Criteria in Solid Tumors were developed using unidimensional measurements, while the World Health Organization criteria were based on bidimensional measurements. Attempts to compare data from the two response criteria have been problematic. There is an ongoing debate regarding the definition of what constitutes response, and there is a need to update the existing criteria. Advances in imaging techniques need to be evaluated and added into new response criteria. As sarcoma patients can derive clinical benefit from therapy without sizable tumor shrinkage, identifying other qualitative changes, such as ossification of osteosarcomas, should also be incorporated into new response criteria. This article reviews existing approaches to assess response criteria in sarcomas, and explores the role of modern imaging in the evaluation of clinical benefit.
Response Evaluation of Gastrointestinal Stromal Tumors
Authors: Choi Haesun
Published: April 2008

Clinical management of patients with gastrointestinal stromal tumors (GISTs) has dramatically changed with the introduction of novel therapeutics, such as imatinib mesylate. This has created a need to re-evaluate the existing criteria used to assess treatment response. The current Response Evaluation Criteria in Solid Tumors are based on unidimensional tumor size, and do not take into account changes in responding GISTs such as a decrease in tumor density and decrease in the number of intratumoral vessels with computed tomography (CT). Positron emission tomography (PET) has been found to be highly sensitive in detecting early response, and to be useful in predicting long-term response to imatinib in patients with metastatic GIST; however, widespread use of PET is limited because of a lack of scanner availability and cost constraints. Modified CT criteria using a combination of tumor density and tumor size are promising in early response evaluation, and have excellent prognostic value. Identifying appropriate treatment response criteria is essential to optimize treatment for patients with GIST.
C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression
Authors: Diel P , Baadners D , Schlüpmann K , Velders M , Schwarz J P
Published: April 2008

Androgens are modulators of skeletal muscle adaptation and regeneration processes. The control of satellite cell activity is a key mechanism during this process. In this study, we analyzed the ability of dihydrotestosterone (DHT) and anabolic steroids to induce and modulate the differentiation of C2C12 myoblastoma cells toward myotubes. C2C12 cells were dose-dependently treated with DHT and anabolic steroids. The time-dependent effects on differentiation were measured and correlated with the expression of genes involved in the regulation of satellite cell activity. The distribution of C2C12 cells within the cell cycle was measured by flow cytometry and differentiation by creatine kinase (CK) activity. Gene expression was analyzed using quantitative real-time PCR and confocal microscopy. The treatment with DHT and anabolic steroids resulted in a stimulation of C2C12 cell proliferation and CK activity. The antiandrogen flutamide was able to antagonize this effect. The expression of the androgen receptor, SOX8, SOX9, Delta, Notch, myostatin, and paired box gene7 (Pax7) was modulated by androgens. The treatment with DHT and anabolic steroids resulted in a strong stimulation of myostatin expression not only in undifferentiated cells but also in myotubes. The stimulation could be antagonized by flutamide. The expression of Pax7 was detectable in C2C12 cells early after treatment with DHT. Our results demonstrate that the key mechanisms of satellite cell differentiation are modulated by androgens. Androgens stimulate the proliferation of C2C12 cells, accelerate the process of differentiation, and increase the expression of myostatin in undifferentiated and differentiated cells. Our findings may have implications not only for the treatment of muscular diseases but also for the improvement of doping analytical methods.
Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells
Authors: Jana Kuladip , Yin Xiangling , Schiffer Randolph B , Chen Jau-Jiin , Pandey Akhilesh K , Stocco Douglas M , Grammas Paula , Wang XingJia
Published: April 2008

During the aging process of males, testosterone biosynthesis declines in testicular Leydig cells resulting in decreases in various physiological functions. To explore the possibility of delaying the decline using food supplements, we have studied steroidogenic effects of a natural flavonoid, chrysin, in mouse Leydig cells. Chrysin dramatically increased cyclic AMP (cAMP)-induced steroidogenesis in MA-10 mouse Leydig tumor cells. This result was confirmed using Leydig cells isolated from mouse testes. The steroidogenic effect of chrysin is not associated with an increase in expression of the P450 side-chain cleavage enzyme, required for the conversion of cholesterol to pregnenolone. In addition, when 22(R)hydroxylcholesterol was used as a substrate, chrysin induced a non-significant increase in steroid hormone, suggesting that the majority of the observed increase in steroidogenesis was due to the increased supply of substrate cholesterol. These observations were corroborated by showing that chrysin induced a marked increase in the expression of steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. Also, chrysin significantly increased StAR promoter activity and StAR mRNA level. Further studies indicated that this compound depressed expression of DAX-1, a repressor in StAR gene transcription. In the absence of cAMP, chrysin did not increase steroidogenesis. However, when a sub-threshold level of cAMP was used, StAR protein and steroid hormone were increased by chrysin to the levels seen with maximal stimulation of cAMP. These results suggest that while chrysin itself is unable to induce StAR gene expression and steroidogenesis, it appears to function by increasing the sensitivity of Leydig cells to cAMP stimulation.
Plasma brain-derived neurotrophic factor daily variations in men: correlation with cortisol circadian rhythm
Authors: Begliuomini Silvia , Lenzi Elena , Ninni Filippo , Casarosa Elena , Merlini Sara , Pluchino Nicola , Valentino Valeria , Luisi Stefano , Luisi Michele , Genazzani Andrea R
Published: April 2008

Expression and secretion of neurotrophins, including brain-derived neurotrophic factor (BDNF), are regulated also by neuronal activity. Data available in the literature suggest that BDNF central levels are influenced by light and dark. Diurnal changes of BDNF mRNA and protein contents have been demonstrated in the rat central nervous system. Based on these pieces of evidence, we investigated the hypothesis of a possible diurnal variation of BDNF circulating levels in human males. Moreover, we looked for a possible correlation with cortisol circadian rhythm, since both BDNF and cortisol are implicated in the maintenance of cerebral functions. In this study, 34 healthy young male volunteers were included. Five blood samples were drawn from each subject thrice in a month at regular 4-h intervals (0800, 1200, 1600, 2000, and 2400 h). BDNF and cortisol were measured in all samples. BDNF was determined by ELISA method. Our results show that plasma BDNF levels, as well as cortisol levels, are significantly higher in the morning when compared with the night (P<0.001), with a trend of constant decrease during the day. Furthermore, plasma BDNF and cortisol are positively correlated (Spearman index=0.8466). The present study is the first to demonstrate the presence of a diurnal rhythm of BDNF in humans. Moreover, the correlation found out between BDNF and cortisol circadian trend allows us to speculate that these two factors may be physiologically co-regulated, in order to maintain the homeostasis of integrated cerebral activities.
Effects of early gestation GH administration on placental and fetal development in sheep
Authors: Wright Casey D , Orbus Ryan J , Regnault Timothy R H , Anthony Russell V
Published: April 2008

Ovine GH (oGH) is synthesized in placental tissue during maximal placental growth and development. Our objectives were to localize oGH mRNA in the placenta, and study the impact of exogenous GH on twin pregnancies during the normal window (35–55 days of gestational age; dGA) of placental expression. In situ hybridization localized oGH mRNA in uterine luminal epithelium but not in tissues of fetal origin. While maternal GH and IGF-I concentrations were increased (P<0.001) approximately tenfold, uterine, uterine fluid, placental, and fetal weights were unaffected by treatment at either 55 or 135 dGA. Fetal length, liver weight, and liver weight per kg of body weight were unaffected by maternal GH treatment. However, in the cotyledon, IGF-binding protein (BP)-1 and IGFBP-4 mRNA concentrations were increased (P<0.05), while IGFBP-2 mRNA was decreased (P<0.05). The concentration of mRNA for IGFBP-3 was unaffected by treatment. Within the caruncle, IGFBP-1 mRNA was decreased (P<0.05), while IGFBP-3 and IGFBP-4 mRNA were increased (P<0.05), and IGFBP-2 mRNA was unchanged due to GH treatment. While our data indicate that elevated maternal GH and IGF-I concentrations during early and mid-gestation do not enhance placental and fetal growth in twin pregnancies, localization of GH mRNA in uterine luminal epithelium could explain GHs transitory expression from 35 to 55 dGA, since by the end of this period the majority of the uterine luminal epithelium has fused with chorionic binucleate cells forming the placental syncytium.
Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases
Authors: Bailey J D , Berardinelli J G , Rocke T E , Bessen R A
Published: April 2008

Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, β-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted β-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrPSc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas.
Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals
Authors: Takei Y , Hashimoto H , Inoue K , Osaki T , Yoshizawa-Kumagaye K , Tsunemi M , Watanabe T X , Ogoshi M , Minamino N , Ueta Y
Published: April 2008

Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0.1–1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na+ concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0.1–1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15–20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activity-modifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10−10–10−9 M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTR+RAMP, to exert central and peripheral cardiovascular actions in mammals.
Orchidectomy increases the formation of non-endothelial thromboxane A2 and modulates its role in the electrical field stimulation-induced response in rat mesenteric artery
Authors: del Campo L , Sagredo A , Aras-López R , Balfagón G , Ferrer M
Published: April 2008

The aim of this study was to analyze whether endogenous male sex hormones influence the release of thromboxane A2 (TXA2) and its role in the electrical field stimulation (EFS)-induced response, as well as the mechanism involved. For this purpose, endothelium-denuded mesenteric arteries from control and orchidectomized male Sprague–Dawley rats were used to measure TXA2 release; EFS-induced response, nitric oxide (NO), norepinephrine (NA), and prostaglandin (PG) I2 release were also measured in the presence of the TXA2 synthesis inhibitor furegrelate. Orchidectomy increased basal and EFS-induced TXA2 release. Furegrelate decreased the EFS-induced contraction in arteries from control rats, but did not modify it in arteries from orchidectomized rats. The EFS-induced neuronal NO release and vasodilator response were increased by furegrelate in arteries from control rats, but were not modified in arteries from orchidectomized rats. Furegrelate did not modify the EFS-induced NA release or vasoconstrictor response in arteries from either control or orchidectomized rats. The EFS-induced PGI2 release was not modified by furegrelate in arteries from control rats, but was increased in arteries from orchidectomized rats. The results of the present study show that endogenous male sex hormone deprivation i) increases non-endothelial TXA2 release and ii) regulates the effect of endogenous TXA2 on the EFS-induced response through different mechanisms that, at the least, involve the NO and PGI2 systems. In arteries from control rats, inhibition of TXA2 formation decreases the EFS-induced response by increasing neuronal NO release. In arteries from orchidectomized rats, the EFS-induced response is unaltered after the inhibition of TXA2 formation, by increasing PGI2 release.
A novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis
Authors: Bujalska I J , Gathercole L L , Tomlinson J W , Darimont C , Ermolieff J , Fanjul A N , Rejto P A , Stewart P M
Published: April 2008

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11β-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11β-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 μM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11β-HSD1 inhibitor PF-877423. 11β-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11β-HSD1 oxo-reductase activity (from nil on day 0 to 5.9±1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11β-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11β-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.
Antioxidants preserve redox balance and inhibit c-Jun-N-terminal kinase pathway while improving insulin signaling in fat-fed rats: evidence for the role of oxidative stress on IRS-1 serine phosphorylation and insulin resistance
Authors: Vinayagamoorthi R , Bobby Zachariah , Sridhar M G
Published: April 2008

The oxidative stress-sensitive c-Jun-N-terminal kinase (JNK) pathway is known to be activated in diabetic condition and is involved in the progression of insulin resistance. However, the effect of antioxidants on JNK pathway and insulin resistance has not been investigated. The present study was aimed to investigate the effect of antioxidants on redox balance, insulin sensitivity, and JNK pathway in high-fat-fed rats. Male Wistar rats were divided into four groups: the control group – received a rodent chow; control+antioxidant group – fed with rodent chow supplemented with 0.2% (w/w) vitamin E, 0.3% (w/w) vitamin C, and 0.5% (w/w) α-lipoic acid; high-fat group – received high-fat diet; and high fat+antioxidant group – fed with high-fat diet supplemented with above antioxidants. Fat feeding to rats for 9 weeks significantly increased IRS-1 serine phoshorylation, reduced insulin-stimulated IRS-1 tyrosine phosphorylation and insulin sensitivity. High-fat diet also impaired redox balance and activated the redox-sensitive serine kinase – JNK pathway. Antioxidant supplementation along with high-fat diet preserved the free radical defense system, inhibited the activation of JNK pathway, and improved insulin signaling and insulin sensitivity. The present study shows for the first time that antioxidants inhibit JNK pathway and IRS-1 serine phosphorylation while improving insulin sensitivity in fat-fed rats. These findings implicate the beneficial effect of antioxidants in obesity-/dyslipidemia-induced insulin resistance in humans.
Perinatal exposure of female rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces central precocious puberty in the offspring
Authors: Kakeyama Masaki , Sone Hideko , Tohyama Chiharu
Published: April 2008

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the fetal and neonatal periods has been indicated to alter the development of the offspring later in life. In this study, we determined whether perinatal exposure to a low dose of TCDD affects the onset of puberty in the female offspring of Long-Evans hooded rats. On day 15 of gestation, pregnant female rats were administered TCDD by gavage at a single dose of 0 (vehicle), 200, or 800 ng/kg b.w. In the female offspring born to dams administered with TCDD at either 200 or 800 ng/kg b.w., the vaginal opening and first estrus occurred ∼4–7 days earlier than in the offspring born to vehicle-treated animals. The ovarian weight gain was also accelerated following exposure to TCDD in a dose-dependent manner. We next examined the ovarian compensatory hypertrophy (OCH) as an indicator of the maturation of the LH/GnRH-generating system in the pituitary and the hypothalamus. Exposure to TCDD accelerated the onset of OCH in the female offspring in a dose-dependent manner. In particular, in the offspring born to the dams exposed to TCDD at 800 ng/kg b.w., hypertrophy, which is characterized by hyperovulation and a marked increase in the weight of the remaining ovary after hemi-ovariectomy, was observed on postnatal days 27–30, which was 10 days earlier than in the offspring born to the vehicle-treated dams. These results indicate that perinatal exposure to a low dose of TCDD induces precocious puberty, including early maturation of the hypothalamic–pituitary axis, the gonads and genitals, in female Long-Evans hooded rats.
Monitoring leptin activity using the chicken leptin receptor
Authors: Hen Gideon , Yosefi Sera , Ronin Ana , Einat Paz , Rosenblum Charles I , Denver Robert J , Friedman-Einat Miriam
Published: April 2008

We report on the construction of a leptin bioassay based on the activation of chicken leptin receptor in cultured cells. A human embryonic kidney (HEK)-293 cell line, stably transfected with the full-length cDNA of chicken leptin receptor together with a STAT3-responsive reporter gene specifically responded to recombinant human and Xenopus leptins. The observed higher sensitivity of chicken leptin receptor to the former is in agreement with the degree of sequence similarity among these species (about 60 and 38% identical amino acids between humans and chickens, and between humans and Xenopus respectively). The specific activation of signal transduction through the chicken leptin receptor, shown here for the first time, suggests that the transition of Gln269 (implicated in the Gln-to-Pro Zucker fatty mutation in rats) to Glu in chickens does not impair its activity. Analysis of leptin-like activity in human serum samples of obese and lean subjects coincided well with leptin levels determined by RIA. Serum samples of pre- and post partum cows showed a tight correlation with the degree of adiposity. However, specific activation of the chicken leptin receptor in this assay was not observed with serum samples from broiler or layer chickens (representing fat and lean phenotypes respectively) or with those from turkey. Similar leptin receptor activation profiles were observed with cells transfected with human leptin receptor. Further work is needed to determine whether the lack of leptin-like activity in the chicken serum samples is due to a lack of leptin in this species or simply to a serum level of leptin that is below the detection threshold.
Low replacement doses of thyroxine during food restriction restores type 1 deiodinase activity in rats and promotes body protein loss
Authors: Araujo Renata Lopes , de Andrade Bruno Moulin , de Figueiredo Álvaro Souto Padron , da Silva Monique Leandro , Marassi Michelle Porto , dos Santos Pereira Valmara , Bouskela Eliete , Carvalho Denise P
Published: April 2008

During food restriction, decreased basal metabolic rate secondary to reduced serum thyroid hormones levels contributes to weight loss resistance. Thyroxine (T4) and 3,3′,5-tri-iodothyronine (T3) administration during caloric restriction produce deleterious side effects; however, the administration of physiological doses of T4 during food restriction has never been evaluated. The aim of this study was to analyze the effects of low replacement doses of T4 in Wistar rats subjected to 40% food restriction. Food restriction for 30 days led to significantly reduced liver type 1 deiodinase activity, serum TSH, leptin, T4, T3, metabolic rate, and body mass. The significant reduction in hepatic deiodinase activity found during food restriction was normalized in a dose-dependent manner by T4 replacement, showing that decreased type 1 deiodinase (D1) activity is secondary to decreased serum thyroid hormone levels during caloric restriction. The lowest replacement dose of T4 did not normalize resting metabolic rate, but was able to potentiate the effects of food restriction on carcass fat loss and did not spare body protein. The highest dose of T4 produced a normalization of daily oxygen consumption and determined a significant reduction in both carcass fat and protein content. Our results show that serum T4 normalization during food restriction restores serum T3 and liver D1 activity, while body protein is not spared. Thus, decreased serum T4 during caloric restriction corresponds to a protective mechanism to avoid body protein loss, highlighting the importance of other strategies to reduce body mass without lean mass loss.