bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of GnRH Dose on Occurrence of Short Oestrous Cycles and LH Response in Cyclic Dairy Heifers
Authors: Rantala MH , Peltoniemi OAT , Katila T , Taponen J
Published: July 2008

Contents

Prostaglandin F2α (PGF2α) and GnRH treatments given 24 h apart have been shown to result in short oestrous cycles (8–12 days) in some cows and heifers. The differences in responses may depend on the dose of GnRH. Therefore, the effect of the dose of GnRH on occurrence of short cycles and LH response was studied here. Oestrus was induced with dexcloprostenol (0.15 mg) in two groups of Ayrshire heifers. A second luteolysis was induced similarly on day 7 after ovulation; 24 h after PGF2α treatment, the heifers were administered either a high (0.5 mg, n = 15, group T500) or low (0.1 mg, n = 10, group T100) dose of gonadorelin. Blood samples for progesterone analyses were collected daily from the second PGF2α administration to the second ovulation after the PGF2α injection. Beginning 24 h after the GnRH treatment, ovaries were examined by transrectal ultrasonography every 6 h until ovulation, and daily between day 4 and the next ovulation. Five heifers from both groups were sampled for LH analyses via a jugular catheter every 30 min from 1 h before to 6 h after the GnRH administration. Short oestrous cycles were detected in 7 of 10 cases in group T100 and in 12 of 15 cases in group T500. No significant differences in LH responses were detected between the groups. In group T500, the rise in LH concentration tended to be somewhat slower than in group T100. The dose of GnRH (0.1 vs 0.5 mg) did not affect the occurrence of short oestrous cycles and LH response.
DECREASED AMPA GLuR2, BUT NOT GLuR3, mRNA EXPRESSION IN RAT AMYGDALA AND DORSAL HIPPOCAMPUS FOLLOWING MORPHINE‐INDUCED BEHAVIOURAL SENSITIZATION
Authors: Sepehrizadeh Zargham , Bahrololoumi Shapourabadi Mina , Ahmadi Shamseddin , Hashemi Bozchlou Saeed , Zarrindast Mohammad‐Reza , Sahebgharani Mousa
Published: July 2008

Repeated administration of psychostimulants and µ‐opioid receptor agonists elicits a progressive enhancement of drug‐induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole proprionic acid (AMPA) receptor function.

In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state‐dependent memory in a passive avoidance test were measured in the presence or absence of 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real‐time reverse transcription–polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine.

The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state‐dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed.

These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium‐permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.
NEGATIVE REGULATION OF QUINONE REDUCTASE 2 BY RESVERATROL IN CULTURED VASCULAR SMOOTH MUSCLE CELLS
Authors: Cai Jing‐Bo , Zhang Zhi‐Hua , Xu Dong‐Jie , Qian Zhi‐Yong , Wang Zhi‐Rong , Huang Yuan‐Zhu , Zou Jian‐Gang , Cao Ke‐Jiang
Published: July 2008

Resveratrol, a polyphenol in red wine, has a cardioprotective effect. Resveratrol‐targeting protein (RTP) has been purified using a resveratrol affinity column (RAC) and has been identified as quinone reductase type 2 (NQO2). We hypothesize that NQO2 is the target protein of resveratrol in vascular smooth muscle cells (VSMC) and that resveratrol inhibits proliferation of VSMC through its action on NQO2. In the present study, we investigated the correlation between NQO2 regulation and cell proliferation in VSMC in response to resveratrol treatment.

The RTP was purified using RAC and was detected with a NQO2 polyclonal antibody. The VSMC were incubated with resveratrol (1, 10 and 50 µmol/L) for 24, 48 and 72 h. Cell proliferation was detected by cell counting and bromodeoxyuridine (BrdU) assay. A lentiviral vector incorporating NQO2 short interference (si) RNA of short hairpin design was constructed and transduced into VSMC. Real‐time quantitative polymerase chain reactionwas used to measure NQO2 mRNA levels; NQO2 expression was determined by western blot analysis.

Using RAC, we extracted a 26 kDa protein from aortic smooth muscle, which was referred to as RTP‐26. Proliferation of VSMC was inhibited by resveratrol in a concentration‐ and time‐dependent manner. The mRNA and protein expression of NQO2 was also repressed by resveratrol in a concentration‐ and time‐dependent manner. A similar pattern of inhibition was observed for cells treated with resveratrol (25 µmol/L) as for cells transduced with a lentiviral vector containing siRNA sequences against NQO2.

Collectively, these data indicate that the suppression of VSMC proliferation mediated by resveratrol correlates with NQO2 downregulation.
NORSOLORINIC ACID INHIBITS PROLIFERATION OF T24 HUMAN BLADDER CANCER CELLS BY ARRESTING THE CELL CYCLE AT THE G0/G1 PHASE AND INDUCING A FAS/MEMBRANE‐BOUND FAS LIGAND‐MEDIATED APOPTOTIC PATHWAY
Authors: Wang Clay CC , Chiang Yi‐Ming , Kuo Po‐Lin , Chang Jiunn‐Kae , Hsu Ya‐Ling
Published: July 2008

Norsolorinic acid, isolated from Aspergillus nidulans, has been shown to have antiproliferative activity in T24 human bladder cancer cells by arresting the cell cycle at the G0/G1 phase and inducing apoptosis. The aim of the present study was to investigate the antiproliferative activity of norsolorinic acid in T24 human bladder cancer cells.

The effects of norsolorinic acid (1, 5, 10 and 20 µmol/L) on the proliferation of T24 cells and on the distribution of cells within different phases of the cell cycle were investigated indirectly using an XTT assay and a flow cytometer, respectively. Factors affecting the cell cycle and apoptosis, including p53, p21, Fas receptor, Fas ligand (FasL) and caspase 8 activity, were examined using ELISA.

The results showed that norsolorinic acid inhibited proliferation of T24 cells in a dose‐dependent manner, with an IC50 of 10.5 µmol/L. The effect involved the induction of cell cycle arrest at the G0/G1 phase and apoptosis.

These results demonstrate that G0/G1 phase arrest is due to increased expression of p21 in cells treated with norsolorinic acid (10 and 20 µmol/L) for 24 h. Moreover, enhanced Fas and membrane‐bound Fas ligand (mFasL) may be responsible for the apoptotic effect of norsolorinic acid. Thus, the present study reports, for the first time, that induction of p21 and the Fas/mFas ligand apoptotic system may participate in the antiproliferative action of norsolorinic acid in T24 human bladder cancer cells.
ROLE OF NAOFEN, A NOVEL WD REPEAT‐CONTAINING PROTEIN, IN REDUCING NITRIC OXIDE‐INDUCED RELAXATION
Authors: Feng Guo‐Gang , Yamada Mitsuru , Wongsawatkul Orapin , Li Chang , Huang Lei , An Jun , Komatsu Toru , Fujiwara Yoshihiro , Naohisa Ishikawa
Published: July 2008

Naofen, a novel WD40 repeat domain‐containing protein, has recently been found in the intracellular compartment. The aim of the present study was to determine whether naofen affects thoracic aortic vascular reactivity in normotensive and hypertensive rats and whether naofen is present in the thoracic aorta. In addition, we examined whether naofen modulates acetylcholine (ACh)‐stimulated nitric oxide (NO) release from the endothelium.

Immunohistochemistry showed greater naofen expression in endothelial cells in the DOCA‐salt group compared with controls. There was increased naofen mRNA expression in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats compared with normotensive rats.

Acetylcholine‐induced relaxation of rat aortic strips was decreased in DOCA‐salt hypertensive rats compared with normotensive rats. Naofen‐N‐ but not naofen‐C‐terminal protein caused a significant decrease in ACh‐induced relaxation of aortic strips from normotensive rats.

Using a nitrite assay in a murine aortic endothelial cell line demonstrated that naofen‐N‐terminal protein, but not naofen‐C‐terminal protein, significantly reduced ACh‐induced NO production, suggesting that naofen interferes with NO production.

Administration of naofen‐N‐terminal protein, but not naofen‐C‐terminal protein, significantly inhibited cyclohydrolase (GCH) I mRNA expression in a murine aortic endothelial cell line, suggesting that naofen‐N‐terminal protein interferes with NO synthesis by inhibiting GCH I mRNA expression.

The results of the present study suggest that naofen is present in vascular endothelial cells and has an inhibitory effect on ACh‐induced relaxation under normotensive conditions. The findings reinforce the functional significance of naofen‐N‐terminal protein on rat vascular reactivity.
ACCELERATED DOSING FREQUENCY OF A PULMONARY FORMULATION OF TISSUE PLASMINOGEN ACTIVATOR IS WELL‐TOLERATED IN MICE
Authors: Stringer Kathleen A , Tobias Meghan , Dunn John S , Campos Jackie , Van Rheen Zachary , Mosharraf Mitra , Nayar Rajiv
Published: July 2008

Tissue plasminogen activator (tPA) has both fibrinolytic and anti‐inflammatory activity. These properties may be useful in treating inflammatory lung diseases, such as acute respiratory distress syndrome (ARDS).

We have previously demonstrated the feasibility of targeted pulmonary delivery of tPA. As part of our research to develop a clinically viable pulmonary formulation of tPA, we assessed the tolerability and incidence of haemorrhage associated with the administration of a pulmonary formulation of mouse tPA (pf‐mtPA).

Intratracheal doses of nebulized pf‐mtPA or sterile saline were administered with increasing frequency to male and female B6C3F1 mice. After dosing, the mice entered a recovery period, after which they were killed and their lungs were lavaged and harvested. Post‐mortem gross necropsy was performed and all major organs were assessed histologically for haemorrhage. The bronchoalveolar lavage fluid was assessed for markers of lung injury.

Mouse tPA that was formulated to mimic a previously characterized human pf‐tPA was well tolerated when given intratracheally with increasing dosing frequency. The administration of pf‐mtPA did not result in any detectable haemorrhagic‐related events or signs of lung injury.

The results of the present longitudinal study demonstrate that a maximally feasible dose of pf‐mtPA (3 mg/kg) can be given frequently over a short period of time (12 h) without haemorrhagic complications. Although these data were generated in a healthy mouse model, they provide support for the continued evaluation of pf‐tPA for the treatment of pulmonary diseases, such as ARDS.
DIFFERENTIAL EFFECTS OF THE ADENOSINE A1 RECEPTOR AGONIST ADENOSINE AMINE CONGENER ON RENAL, FEMORAL AND CAROTID VASCULAR CONDUCTANCE IN PRETERM FETAL SHEEP
Authors: Booth Lindsea C , Tummers Leonie , Jensen Ellen C , Barrett Carolyn J , Malpas Simon C , Gunn Alistair J , Bennet Laura
Published: July 2008

Adenosine A1 receptor activation is critical for endogenous neuroprotection from hypoxia–ischaemia, raising the possibility that treatment with A1 receptor agonists may be an effective physiological protection strategy for vulnerable preterm infants. However, the A1 receptor can mediate unwanted systemic effects, including vasoconstriction of the afferent glomerular arteriole. There is limited information on whether this occurs at doses that improve cerebral perfusion in the immature brain.

Therefore, in the present study, we examined whether infusion of the selective A1 receptor agonist adenosine amine congener (ADAC) is associated with reduced renal perfusion in chronically instrumented preterm (0.7 gestation) fetal sheep. In the present study, ADAC was given in successive doses of 2.5, 5.0 and 15.0 µg, 45 min apart.

Treatment with ADAC was associated with a marked reduction in renal vascular conductance (and blood flow), whereas carotid conductance was increased and there was no significant effect on femoral conductance. In contrast with the stable effects of increasing ADAC dose on vascular conductance, there was a significant dose‐related fall in fetal heart rate and blood pressure.

In conclusion, these short‐term data support the concern that A1 receptor agonist infusion can selectively impair renal perfusion, even at low doses.
GLUCOSE REGULATION OF DIPEPTIDYL PEPTIDASE IV GENE EXPRESSION IS MEDIATED BY HEPATOCYTE NUCLEAR FACTOR‐1α IN EPITHELIAL INTESTINAL CELLS
Authors: Gu Ning , Tsuda Mariko , Matsunaga Tetsuro , Adachi Tetsuya , Yasuda Koichiro , Ishihara Akihiko , Tsuda Kinsuke
Published: July 2008

Dipeptidyl peptidase IV (DPP‐IV) is a new drug target in the treatment of Type 2 diabetes. Dipeptidyl peptidase IV enzyme activity is significantly altered in Type 2 diabetic patients with hyperglycaemia, but the underlying molecular mechanisms remain unclear.

The first aim of the present study was to clarify whether glucose regulates DPP‐IV enzyme activity. To address this, DPP‐IV gene expression and enzyme activity were measured in Caco2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) concentrations of glucose. We observed that high glucose inhibited DPP‐IV gene expression and enzyme activity.

The second aim of the present study was to investigate whether hepatocyte nuclear factor (HNF)‐1α contributes to glucose regulation of DPP‐IV gene expression. To explore this question, associations between the gene expression of DPP‐IV and HNF‐1α were examined in Caco‐2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) glucose. We found that the pattern of glucose‐regulated DPP‐IV gene expression is similar to that of HNF‐1α. Moreover, to elucidate whether glucose regulation of DPP‐IV gene expression is affected when HNF‐1α is inhibited, we produced two stable cell lines in which a dominant‐negative mutant HNF‐1αR271G or basic vectors were stably expressed. We found that glucose regulation of DPP‐IV gene expression was compromised in HNF‐1αR271G cells, but was well maintained in basic vector cells.

These results suggest that glucose regulation of DPP‐IV gene expression is mediated by HNF‐1α.
GASTROINTESTINAL ENDOCANNABINOID SYSTEM: MULTIFACETED ROLES IN THE HEALTHY AND INFLAMED INTESTINE
Authors: Smid Scott D
Published: July 2008

The endogenous cannabinoid (endocannabinoid) system is emerging as a key modulator of intestinal physiology, influencing motility, secretion, epithelial integrity and immune function in the gut, in addition to influencing satiety and emesis.

Accumulating evidence suggests that the endocannabinoid system may play a pivotal role in the pathophysiology of gastrointestinal disease, particularly in the light of recent studies demonstrating an effect of endocannabinoids on the development of experimental inflammation and linkages with functional clinical disorders characterized by altered motility.

The predominant endocannabinoids, anandamide and 2‐arachidonoylglycerol, not only mediate their effects via two recognized cannabinoid receptor subtypes, namely CB1and CB2, but emerging evidence now shows they are also substrates for cyclo‐oxygenase (COX)‐2, generating a distinct and novel class of prostaglandin ethanolamides (prostamides) and prostaglandin glycerol esters. These compounds are bioactive and may mediate an array of biological effects distinct to those of conventional prostanoids.

The effects of prostamides on gastrointestinal motility, secretion, sensation and immune function have not been characterized extensively. Prostamides may play an important role in gastrointestinal inflammation, particularly given the enhanced expression of both COX‐2 and endocannabinoids that occurs in the inflamed gut.

Further preclinical studies are needed to determine the therapeutic potential of drugs targeting the endocannabinoid system in functional and inflammatory gut disorders, to assist with the determination of feasibility for clinical translation.
MECHANISMS OF FATIGUE INDUCED BY ISOMETRIC CONTRACTIONS IN EXERCISING HUMANS AND IN MOUSE ISOLATED SINGLE MUSCLE FIBRES
Authors: Place Nicolas , Bruton Joseph D , Westerblad Håkan
Published: July 2008

Muscle fatigue (i.e. the decrease in muscle performance during exercise) has been studied extensively using a variety of experimental paradigms, from mouse to human, from single cell to whole‐body exercise. Given the disparity of models used to characterize muscle fatigue, it can be difficult to establish whether the results of basic in vitro studies are applicable to exercise in humans.

In the present brief review, our attempt is to relate neuromuscular alterations caused by repeated or sustained isometric contraction in humans to changes in excitation–contraction (E‐C) coupling observed in intact single muscle fibres, where force and the free myoplasmic [Ca2+] can be measured.

Accumulated data indicate that impairment of E‐C coupling, most likely located within muscle fibres, accounts for the fatigue‐induced decrease in maximal force in humans, whereas central (neural) fatigue is of greater importance for the inability to continue a sustained low‐intensity contraction. Based on data from intact single muscle fibres, the fatigue‐induced impairment in E‐C coupling involves: (i) a reduced number of active cross‐bridges owing to a decreased release of Ca2+; (ii) a decreased sensitivity of the myofilaments to Ca2+; and/or (iii) a reduced force produced by each active cross‐bridge.

In conclusion, data from single muscle fibre studies can be used to increase our understanding of fatigue mechanisms in some, but not all, types of human exercise. To further increase the understanding of fatigue mechanisms in humans, we propose future studies using in vitro stimulation patterns that are closer to the in vivo situation.
Evaluation of angiogenesis in 77 pituitary adenomas using endoglin as a marker
Authors: Pizarro Cristina B. , Oliveira Miriam C. , Pereira‐Lima Julia F.S. , Leães Carolina G.S. , Kramer Carolina K. , Schuch Tiago , Barbosa‐Coutinho Lígia M. , Ferreira Nelson P.
Published: July 2008

Angiogenesis, a fundamental process for the development and growth of a tumor, is less expressive in adenomas than in the normal pituitary tissue. There is controversy about the behavior of angiogenesis as a function of hormonal secretion or other characteristics of pituitary tumors. Endoglin (CD105) is a proliferation‐associated antigen on endothelial cells, as well as an endothelial progenitor cell marker. We used the anti‐endoglin antibody, a glycoprotein expressed in endothelial cells and conjunctive tissue, as a new marker particularly associated with neovascularization, in order to determine microvascular density (MVD) in pituitary adenomas. There were 77 samples, 31 males and 46 females, carriers of micro‐ (n = 24) or macroadenomas (n = 53). No significant difference was found in MVD concerning the variables of age, clinical presentation, and immunohistochemical phenotype or tumor size. MVD in males (median 5.4) was significantly higher (P = 0.001) than in females (median 3.0). Cell proliferation, as evaluated by the MIB‐1 antibody (a cellular proliferation index [Ki‐67 antigen], which is present in all stages of the cellular cycle except for the resting cells), ranged from 0% to 19.58%. No correlation was found between MIB‐1 and MVD. It is possible to infer that the lower MVD found in pituitary adenomas in females reflects an inhibitory estrogen action on TGF‐β1, a protein involved in vascular remodeling. Because of its role as a TGF receptor ligand, endoglin proved to be sensitive in detecting this gender difference in pituitary tumor angiogenesis.
Solitary subependymal giant cell astrocytoma incidentally found at autopsy in an elderly woman without tuberous sclerosis complex
Authors: Takei Hidehiro , Adesina Adekunle M. , Powell Suzanne Z.
Published: July 2008

Subependymal giant cell astrocytoma (SEGA) is a benign, slowly growing tumor typically occurring in the setting of tuberous sclerosis complex (TSC). However there are several reported cases in which patients with a solitary SEGA had no other stigmata of TSC. We describe a case of SEGA in a 75‐year‐old woman representing the oldest patient reported to‐date. The patient had a history of radical vulvectomy for malignant melanoma (MM), and died of autopsy‐confirmed widespread systemic metastasis. Postmortem examination of the brain revealed a single 2.1 × 1.0 × 0.8 cm intraventricular nodule in the lateral ventricle. Histologically, it was composed of interlacing bundles of spindle‐shaped tumor cells with thin delicate processes admixed with relatively large pleomorphic cells with abundant glassy eosinophilic cytoplasm, as seen in a SEGA. Immunohistochemically, GFAP, S‐100 protein, and neuron specific enolase were positive, and synaptophysin labeled a few tumor cells. Also noted were rare isolated MM cells within the tumor (i.e., tumor‐to‐tumor metastasis). Autopsy showed no manifestations of TSC systemically or intracranially. The histopathological differential diagnosis was limited and included giant cell ependymoma and, much less likely, giant cell glioblastoma and pleomorphic xanthoastrocytoma. This case illustrates that SEGA can be found incidentally in an elderly individual with no associated symptoms and also indicates that SEGA can occur outside the setting of TSC. Tumor metastasis to an occult SEGA is extremely rare.
Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young adult rats
Authors: Silvagni Alessandra , Barros Virginia G. , Mura Cristina , Antonelli Marta C. , Carboni Ezio
Published: July 2008

Gestational stress [prenatal stress (PNS)] has been associated with low birth weight, preterm delivery, and higher vulnerability to psychiatric disorders such as schizophrenia, depression or attention deficit with hyperactivity disorder. The alteration of catecholamine transmission has been attributed a major role in the etiology of psychiatric disturbances. We investigated the effect of PNS on basal and stimulated dopamine and noradrenaline output in the nucleus accumbens of freely moving adolescent and young adult rats (30–35 and 60–70 postnatal days respectively) because of the importance of this area in drug dependence and possibly in psychiatric disorders that are treated with drugs that act on dopamine and noradrenaline transmission. Stimulation was obtained with intraperitoneal amphetamine (0.25 mg/kg) or subcutaneous nicotine (0.4 mg/kg). The results showed the following: (i) basal and amphetamine‐stimulated dopamine output in adolescent and adult PNS rats is higher than in controls; (ii) nicotine‐stimulated dopamine output is lower than in controls in adolescent but not in adult PNS rats; (iii) basal noradrenaline output is lower than in controls in adolescent but not in adult PNS rats; (iv) amphetamine‐stimulated noradrenaline output is higher than in controls in adult but not in adolescent PNS rats; (v) nicotine‐stimulated noradrenaline output in PNS rats is higher than in controls, although only in adults. These results show that PNS may produce a complex change in accumbal dopamine and noradrenaline transmission. We discuss the possibility that these changes might be correlated with the development of psychiatric disorders or with an increased vulnerability to drug addiction.
Stromal‐cell‐derived factor 1α /CXCL12 modulates high‐threshold calcium currents in rat substantia nigra
Authors: Guyon A. , Skrzydelski D. , Rovère C. , Apartis E. , Rostène W. , Kitabgi P. , Mélik Parsadaniantz S. , Nahon J. L.
Published: July 2008

Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal‐cell‐derived factor 1α (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated. We tested the effects of CXCL12 on whole‐cell currents of dopaminergic neurons recorded in patch clamp in substantia nigra slices and showed that CXCL12 (0.01–10 nm) increased the amplitude of total high‐voltage‐activated (HVA) Ca currents through CXCR4 activation. This effect was reversibly reduced by ϖ‐conotoxin‐GVIA, suggesting that CXCL12 acted on N‐type Ca currents, known to be involved in dopamine (DA) release. We therefore investigated the effects of CXCL12 on DA release from cultured dopaminergic neurons from the rat mesencephalon. In basal conditions, CXCL12 alone had no effect on DA release. When neurons were depolarized with KCl (20 mm), and thus when HVA Ca currents were activated, low CXCL12 concentrations (1–50 nm) increased DA release via CXCR4 stimulation. These data strongly suggest that the chemokine CXCL12 can act directly as a neuromodulator of dopaminergic neuronal electrical activity through the modulation of HVA currents.
An attractor hypothesis of obsessive–compulsive disorder
Authors: Rolls Edmund T. , Loh Marco , Deco Gustavo
Published: July 2008

We propose a top‐down approach to the symptoms of obsessive–compulsive disorder (OCD) based on a statistical dynamical framework. An increased depth in the basins of attraction of attractor network states in the brain makes each state too stable, so that it tends to remain locked in that state and can not easily be moved on to another state. We suggest that the different symptoms that may be present in OCD could be related to changes of this type in different brain regions. For example, the difficulty in attentional and cognitive set switching could be related to networks operating in this way in the prefrontal cortex. Repetitive actions and a difficulty in moving to new actions could be related to overstability in networks in the higher order motor, including cingulate areas. In integrate‐and‐fire network simulations, an increase in the N‐methyl‐d‐aspartate (NMDA) and/or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor conductances, which increases the depth of the attractor basins, increases the stability of attractor networks, and makes them less easily moved on to another state by a new stimulus. Increasing γ‐aminobutyric acid (GABA)‐receptor activated currents can partly reverse this overstability. There is now some evidence for overactivity in glutamate transmitter systems in OCD, and the hypothesis presented here shows how some of the symptoms of OCD could be produced by the increase in the stability of attractor networks that is produced by increased glutamatergic activity.
Pain relief as an opponent process: a psychophysical investigation
Authors: Leknes Siri , Brooks Jonathan C. W. , Wiech Katja , Tracey Irene
Published: July 2008

Relief from pain in humans is frequently measured by computing the reduction on an 11‐point pain intensity scale. However, this definition of relief may be insufficient to capture the utility of pain relief for the individual. Based on pain literature and evidence from studies examining relief and reward, it is clear that pain relief is a broad concept comprising several factors, only one of which is pain intensity reduction. According to opponent process theory, all sensations consist of a primary process and a slow ‘opponent process’ of opposite valence, the purpose of which is to reduce the deviation from homeostatic balance. Here, opponent process theory provided a framework to explore the interaction between pain, relief and reward. We devised three psychophysical studies examining the temporal (Experiment I) and magnitude (Experiments I and II) relationships between pain severity and its subsequent relief. In Experiment III, we further manipulated the magnitude and pleasantness of relief experienced by applying innocuous cooling following noxious heat stimulation of capsaicin‐sensitized skin. Results confirmed predictions from opponent process theory and showed that pain intensity reduction was significantly stronger than relief intensity ratings. Furthermore, continuous relief ratings appeared to reflect the speed of pain intensity reduction. Varying pain intensity parametrically confirmed that relief increases with pain intensity. That innocuous cooling following primary hyperalgesia intervention significantly increased the intensity, pleasantness and duration of relief provides further evidence that pain relief encapsulates more than a reduction in pain intensity. Importantly, the high relief pleasantness ratings confirmed the hypothesized link between relief and reward.
The brain‐derived neurotrophic factor receptor TrkB is critical for the acquisition but not expression of conditioned incentive value
Authors: Johnson Alexander W. , Chen Xi , Crombag Hans S. , Zhang Chao , Smith Dani R. , Shokat Kevan M. , Gallagher Michela , Holland Peter C. , Ginty David D.
Published: July 2008

Stimuli paired with reward acquire incentive properties that are important for many aspects of motivated behavior, such as feeding and drug‐seeking. Here we used a novel chemical–genetic strategy to determine the role of the brain‐derived neurotrophic factor (BDNF) receptor TrkB, known to be critical to many aspects of neural development and plasticity, during acquisition and expression of positive incentive value by a cue paired with food. We assessed that cue’s learned incentive value in a conditioned reinforcement task, in which its ability to reinforce instrumental responding later, in the absence of food itself, was examined. In TrkB F616A knock‐in mice, TrkB kinase activity was suppressed by administering the TrkB inhibitor 1NMPP1 during the period of initial cue incentive learning only (i.e. Pavlovian training), during nose‐poke conditioned reinforcement testing only, during both phases, or during neither phase. All mice acquired cue–food associations as indexed by approach responses. However, TrkB F616A mice that received 1NMPP1 during initial cue incentive learning failed to show conditioned reinforcement of nose‐poking, regardless of their treatment in testing, whereas administration of 1NMMP1 only during the testing phase had no effect. The effects of 1NMPP1 administration were due to inhibition of TrkBF616A, because the performance of wild‐type mice was unaffected by administration of the compound during either phase. These data indicate that BDNF or NT4 signaling through TrkB receptors is required for the acquisition of positive incentive value, but is not needed for the expression of previously acquired incentive value in the reinforcement of instrumental behavior.
Spontaneous discharge characteristic of neurons in the ventromedial nucleus of the rat hypothalamus in vivo
Authors: Sabatier Nancy , Leng Gareth
Published: July 2008

The ventromedial nucleus of the hypothalamus (VMN) is one of the main central regulators of two vital behaviours in rat: feeding behaviour and sexual behaviour. To better understand how these behaviours are regulated in the brain requires assessing how physiological stimuli are encoded by the electrical activity of populations of neurons, but there is still little known about the electrical activity of neurons in the VMN, in particular how it is regulated in vivo. Here, we recorded spontaneous firing activity from single VMN neurons in urethane‐anaesthetized rats in vivo, and characterized their electrophysiological identities. For each of 271 cells, we constructed hazard functions from interspike interval histograms to show how the excitability of the cell changes with time after a spike. We completed the statistical characterization of each cell by analysis of its mean firing rate and coefficient of variation, and features of its interspike interval distribution, including kurtosis and skew (around the mean and around the mode). We thereby identified nine subpopulations of neurons in the VMN, which we named according to the main features of their firing pattern. One of the subpopulations fires very regularly, another almost randomly and another in intermittent clusters of two–three spikes, but perhaps the most interesting subpopulation are ‘oscillatory cells’ whose activity seems to be governed by an extrinsic 3‐Hz rhythm. Whether these electrophysiologically distinct populations are also functionally and neurochemically distinct has now to be tested.
Chronic pain in children in the UK: a survey of pain clinicians and general practitioners
Authors: BHATIA ANUJ , BRENNAN LIAM , ABRAHAMS MARK , GILDER FAY
Published: July 2008

Background:  There is a lack of information about the prevalence, manifestations, and management of chronic pain in children in the UK. We surveyed consultants with an interest in chronic pain management and general practitioners (GPs) in the UK in order to understand their perspective on chronic pain in children.

Methods:  We conducted a postal survey of clinicians with an interest in chronic pain management and GPs in the UK. The survey contained questions relating to the following aspects of managing children with chronic pain: (i) clinicians’ training and experience; (ii) available resources; (iii) perceived prevalence, presentation, and referral patterns; (iv) interventions; and (v) outcomes.

Results:  472 pain clinicians and 131 GPs were contacted. The response rates were 55% and 61% respectively. Of the respondents, 77% of pain clinicians and 95% of GPs acknowledged a lack of adequate training for managing children with chronic pain. 57% of the pain clinicians and 63% of the GPs reported that the prevalence of chronic pain in children was <5%. In the comments section, 22% of those respondents who frequently manage children with chronic pain reported an increase in the incidence of this problem over the last 5 years. The common chronic pain syndromes in children were reported to be: musculoskeletal and limb pain, recurrent abdominal and pelvic pain, and headache. 15% of the respondents advised that children with chronic pain would be best managed in specialist pediatric centers and 75% opined that majority of children with chronic pain have a fair to good prognosis.

Conclusions:  More information is required about prevalence, manifestations and long‐term effects of chronic pain in children in the UK. There is a need for increasing training and resources amongst GPs and pain clinicians for managing chronic pain in the pediatric age group.
Cerebral hemispherectomy in infants and young children
Authors: FLACK SEAN , OJEMANN JEFF , HABERKERN CHARLES
Published: July 2008

Background:  Children with seizure disorders unresponsive to medical management may undergo surgical disconnection of a cerebral hemisphere, or hemispherectomy, in order to reduce or eliminate seizures. Because early cessation of seizures is thought to improve developmental outcomes, infants and young children with intractable seizures are undergoing hemispherectomies with increasing frequency. Previously, these procedures have been noted to be accompanied by severe cardiovascular, pulmonary, neurologic and coagulopathic complications. Newer surgical techniques (i.e. ‘functional’ rather than ‘anatomic’ hemispherectomy) and improved anesthetic management may reduce the perioperative complication rate of this procedure. The aim of this case series was to determine the incidence of major complication of functional hemispherectomy in our institution.

Methods:  A retrospective chart review was conducted of all children <3 years of age undergoing functional hemispherectomies for intractable seizures over a 4‐year period at our institution.

Results:  Seven children were identified. No serious cardiovascular, pulmonary, neurologic or coagulopathic adverse events occurred. Perioperative blood loss and its sequelae were the most common complication. Postoperative management was generally uncomplicated, although one patient required readmission to the ICU for treatment of diabetes insipidus. All children survived and, at latest follow‐up, all but one remained seizure‐free.

Conclusion:  This small case series suggests that improvements in anesthetic and surgical techniques may be associated with a decreased complication rate for infants and small children undergoing seizure surgery than previously reported.
Blood pressure changes associated with sibutramine and weight management – an analysis from the 6‐week lead‐in period of the sibutramine cardiovascular outcomes trial (SCOUT)*
Authors: Sharma A. M. , Caterson I. D. , Coutinho W. , Finer N. , Van Gaal L. , Maggioni A. P. , Torp‐Pedersen C. , Bacher H. P. , Shepherd G. M. , James W. P. T. ,   SCOUT Investigators
Published: July 2008

Objective:  To explore vital sign changes among patient subgroups during the 6‐week lead‐in period of the sibutramine cardiovascular outcomes (SCOUT) trial.

Methods:  SCOUT is an ongoing, double‐blind, randomized, placebo‐controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. During the 6‐week lead‐in period, 10 742 patients received sibutramine and weight management. Vital sign changes were assessed post hoc by initial blood pressure (mmHg) categorized as normal (<130/<85), high‐normal (130 to <140/85 to <90) or hypertensive (≥140/≥90); weight change categories (weight gain/no weight change, >0 to 2.5% weight loss, >2.5 to 5% weight loss and >5% weight loss) and current antihypertensive medication class use (none, one, or two or more). To assess the impact of sibutramine on blood pressure and pulse rate, only patients (N = 10 025) who reported no change in the class of antihypertensive medication used and who did not report an increase in antihypertensive medication use were analysed.

Results:  At entry, approximately 50% of patients were hypertensive and 26% were high‐normal. In hypertensive patients, blood pressure changes (mmHg) decreased by median [5th, 95th percentile] of −6.5 systolic [−27.0, 8.0] and −2.0 diastolic [−15.0, 8.0] (p < 0.001). Hypertensive patients with no weight loss or with weight gain had median decreases of −3.5 systolic [−26.0, 10.0] and −1.5 diastolic [−16.0, 9.0] (p < 0.001). Normotensive patients had median increases of 1.5 systolic [−15.0, 19.5] and 1.0 diastolic [−10.5, 13.0] (p < 0.001) attenuated with increasing weight loss. Approximately 43% of patients initially categorized as hypertensive had a lower blood pressure category at end‐point. Concomitant antihypertensive medication classes did not affect blood pressure reductions. Pulse rates were uniformly elevated (median 1–4 bpm, p < 0.001) across blood pressure and weight change categories.

Conclusions:  In hypertensive patients (≥140/≥90), blood pressure decreases were observed during 6‐week treatment with sibutramine even when body weight was unchanged. In patients with normal blood pressure (<130/<85), weight loss of >5% induced decreases in systolic blood pressure; otherwise, small increases were observed. Small pulse rate increases were observed regardless of blood pressure or weight change status.
Thiazolidinedione‐induced skeletal fragility – mechanisms and implications
Authors: Grey Andrew
Published: July 2008

Recent evidence suggests that the risk of several types of fracture is increased in type 2 diabetes mellitus (T2DM). Thiazolidinediones (TZDs) are now widely used in the management of T2DM, and their use may increase in other diseases characterized by insulin resistance. The PPAR‐γ, the molecular target of the TZDs currently in clinical use, is expressed in skeletal tissue. Evidence from preclinical studies has demonstrated that activation of PPAR‐γ (i) inhibits bone formation by diverting mesenchymal stem cells from the osteogenic to the adipocytic lineage and (ii) may increase bone resorption by stimulating the development of osteoclasts. There is also potential for indirect adverse skeletal effects of PPAR‐γ activation by modulation of circulating levels of hormones and cytokines known to influence bone metabolism. Recent studies in humans have demonstrated that TZDs decrease markers of bone formation decrease bone mass, and increase fracture rates, at least in women. The implication of these findings is that fracture risk should be considered in patients with T2DM for whom TZD therapy is being considered, and appropriate therapy instigated to prevent fractures in individuals ascertained to be at high risk.
Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report
Authors: Abraira C. , Duckworth W. C. , Moritz T.
Published: July 2008

Objective:  The Veterans Affairs Diabetes Trial (VADT) will assess the effect of intensive (INT) vs improved standard (STD) glycaemic control on major cardiovascular (CV) events, treating other risk factors equally in both arms. Four‐year results of main metabolic parameters are presented.

Research design and methods:  VADT is a 7.5 years prospective randomized study of 1791 patients, 20 centres, of men and women of age 60.5 ± 8.7 years, diagnosed for 11.5 ± 7.5 years. Their body mass index (BMI) at baseline was 31 ± 4 kg/m2 and mean A1C 9.4 ± 1.5% after maximum dose of oral agents or insulin treatment. Step treatment consists of glimepiride or metformin, rosiglitazone, insulin and other agents; A1C goals are 8–9% in STD and <6% in INT. Lifestyle, blood pressure and lipids are treated uniformly in both arms.

Results:  A1C improved in both arms. INT kept median A1C <7% all years, A1C separation is 1.5–1.7%. From year 1 to 4, mean blood pressure is <129/74 mmHg, similar throughout. Median LDL‐C was <97 mg/dl by year 1 and triglycerides 150 or less by 2 years. Triglycerides were lower in INT (12–16 mg/dl; p < 0.01). By 4 years, 88% are on lipid‐lowering agents and 93% are on antiplatelet/anticoagulant agents. BMI is higher in INT every year (0.9–1.6 kg/m2; p < 0.01).

Conclusion:  VADT is maintaining the expected A1C in both STD and INT, and LDL‐C, triglycerides and blood pressure are at target. The trial is continuing to June 2008. It will be the first long‐term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments.
The thyroid hormone derivative 3‐iodothyronamine increases food intake in rodents
Authors: Dhillo W. S. , Bewick G. A. , White N. E. , Gardiner J. V. , Thompson E. L. , Bataveljic A. , Murphy K. G. , Roy D. , Patel N. A. , Scutt J. N. , Armstrong A. , Ghatei M. A. , Bloom S. R.
Published: July 2008

Background:  The thyroid hormone derivative 3‐iodothyronamine (T1AM), an endogenous biogenic amine, is a potent agonist of the G protein–coupled trace amine‐associated receptor 1 (TAAR1). T1AM is present in rat brain, and TAAR1 is expressed in hypothalamic nuclei associated with the regulation of energy homeostasis.

Aim:  The aim of this study was to determine the effects of T1AM on food intake in rodents.

Methods:  We determined the effect of (i) intraperitoneal (i.p.) administration of T1AM on food intake, oxygen consumption (VO2) and locomotor activity in mice; (ii) intracerebroventricular (ICV) injection of T1AM on food intake in male rats; (iii) c‐fos expression following ventricular administration of T1AM in male rats; and (iv) direct injection of T1AM into the arcuate nucleus (ARC) of male rats on food intake.

Results:  (i) T1AM (4 nmol/kg) significantly increased food intake following i.p. injection in mice but had no effect on VO2 or locomotor activity. (ii) ICV administration of T1AM (1.2 nmol/kg) significantly increased food intake in male rats. (iii) Intraventricular administration of T1AM significantly increased c‐fos expression in the ARC of male rats. (iv) Direct administration of T1AM (0.12, 0.4 and 1.2 nmol/kg) into the ARC of male rats significantly increased food intake.

Conclusion:  These data suggest that T1AM is an orexigenic factor that may act through the ARC to increase food intake in rodents.
Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations
Authors: Morales Alvaro , Black Angela M. , Emerson Laurel E.
Published: July 2008

OBJECTIVE

To assess the effects of testosterone supplementation in men with testosterone deficiency syndrome (TDS) after external beam radiotherapy (EBRT) for localized prostate cancer.

PATIENTS AND METHODS

Five men with significant signs of TDS after treatment for localized prostate cancer with EBRT were treated with testosterone once their prostate‐specific antigen (PSA) level had reached the nadir.

RESULTS

The mean (range) level of testosterone before supplementation was 5.2 (1.1–9.2) nmol/L and the duration of follow‐up while on supplementation was 14.5 (6–27) months. At the last visit, the testosterone levels were 17.6 (8.5–32.4) nmol/L. One of the five patients had a transitory increase in PSA level but none had levels of >1.5 ng/mL. All patients reported a marked response in the manifestations of TDS, i.e. four each reported decreased hot flushes, decreased fatigue and improved libido, and two reported improved erectile function.

CONCLUSION

Men with TDS after EBRT for localised prostate cancer are candidates for testosterone therapy. The patients must be aware of the advantages and disadvantages of the treatment. PSA levels must have reached a nadir before starting treatment and the follow‐up must be particularly close. In these few patients there were no adverse effects from testosterone supplementation. There is a need for more information about the safety and efficacy of testosterone therapy in men successfully treated for localized prostate cancer, because there is evidence indicating hypogonadism in these patients, compromising their quality of life and longevity, independent of the cancer.
Risk factors for mortality and morbidity related to radical cystectomy
Authors: Boström Peter J. , Kössi Jyrki , Laato Matti , Nurmi Martti
Published: July 2008

OBJECTIVES

To evaluate the risk factors for mortality and morbidity related to radical cystectomy (RC) in a medium‐sized academic centre, and to analyse the rate and trends of perioperative morbidity and mortality, as although complications related RC to are lower in modern than historic series, RC is still associated with marked risks.

PATIENTS AND METHODS

The study included 258 patients undergoing RC for bladder cancer in Turku University Hospital in 1986–2005. Basic patient characteristics and in‐hospital, early (from hospital discharge to 3 months) and combined morbidity and mortality were analysed. Risk analysis included 16 risk factors for complications. Trends were analysed by comparing the two study decades (1986–1995 vs 1996–2005).

RESULTS

The total complication rate was 34%, with minor and major complications in 26%, and 11% of patients, respectively. There were no significant changes in total morbidity, but the number of myocardial infarctions and atrial fibrillations decreased significantly (P = 0.045). Operative mortality was 2.7%, with an insignificant decrease (4.2% to 0.9%, P = 0.11) over time. Salvage RC, high American Society of Anesthesiologists (ASA) score (≥3), extensive blood loss (>3 L), a high number of transfusions (five or more), several comorbidities (two or more), age (≥65 vs <65 years), and extravesical tumours were significant risk factors for major complications. An ASA score of ≥3 and five or more transfusions were the only factors associated with mortality. A high ASA score (odds ration 3.25, 95% confidence interval 1.08–9.74) and high number of transfusions (2.74, 1.05–7.15) were independent risk factors for major complications.

CONCLUSION

Although RC is associated with acceptable morbidity, attention should be given to risk factors identified at the time of patient selection, and to meticulous haemostasis at the time of surgery. A predictable outcome comparable to that in high‐volume centres is also possible in a medium‐sized hospital.