Growth of long range forward-backward multiplicity correlations with centrality in Au + Au collisions at square root of sNN = 200 GeV.

Forward-backward multiplicity correlation strengths have been measured with the STAR detector for Au + Au and p + p collisions at square root of s(NN) = 200 GeV. Strong short- and long-range correlations (LRC) are seen in central Au + Au collisions. The magnitude of these correlations decrease with decreasing centrality until only short-range correlations are observed in peripheral Au + Au collisions. Both the dual parton model (DPM) and the color glass condensate (CGC) predict the existence of the long-range correlations. In the DPM, the fluctuation in the number of elementary (parton) inelastic collisions produces the LRC. In the CGC, longitudinal color flux tubes generate the LRC. The data are in qualitative agreement with the predictions of the DPM and indicate the presence of multiple parton interactions.

Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines.

Human activated T cells adhere to synovial fibroblast-like cells in vitro. The present study was conducted to investigate the consequences of T cell-synovial fibroblast interactions with regard to induction of adhesion molecules and proinflammatory cytokines. A sensitive Western blot technique, polymerase chain reaction (PCR) amplification, and fluorescence-activated cell sorter (FACS) analysis were used to analyze the induction of VCAM-1 and ICAM-1 expression in T cell-synovial fibroblast cocultures. VCAM-1 and ICAM-1 expression could be induced in synovial fibroblast-like cells by 2 h. PCR amplification showed that both forms of VCAM-1 mRNA are found after the interaction of synovial fibroblasts with T cells. Up-regulation of VCAM-1 and ICAM-1 was confined to synovial fibroblasts; T cells did not express VCAM-1 or increased ICAM-1. In contrast to the T cell-synoviocyte interaction, the interaction between T cells and dermal fibroblasts resulted in the up-regulation of ICAM-1 but not VCAM-1, suggesting tissue-specific regulation of VCAM-1. The T cell-synovial fibroblast interaction also resulted in increased levels of tumor necrosis factor (TNF), interferon-gamma, and interleukin-6 in coculture supernatant. Of the neutralizing antibodies used against these cytokines, only anti-TNF could significantly inhibit VCAM-1 and ICAM-1 expression. When T cells were separated from synoviocytes by a chamber that allowed medium exchange but no cell contact, VCAM-1 and ICAM-1 failed to be up-regulated and cytokine accumulation in cocultures was drastically reduced. Our results demonstrate mutual cell activation of T cells and synoviocytes upon cell contact as shown by the release of T cell- and synoviocyte-specific cytokines and suggest a cell contact-mediated and T cell-initiated mechanism for the chronic accumulation and retention of mononuclear cells via VCAM-1/ICAM-1 by synovial fibroblasts in the rheumatoid synovium.

The release of soluble p55 TNF receptor from U937 cells studied by a new p55 immunoassay.

A highly specific and sensitive immunoassay for soluble p55 tumor necrosis factor receptor (TNFR) has been established. The immunoassay was based on a newly developed monoclonal antibody (IV4E) recognizing a non-TNF-binding site of the p55 TNFR. The IV4E antibody immunoprecipitated a 55 kDa TNF binding protein from HL-60 cells. No binding of IV4E to the p75 TNFR could be detected. Bound TNFR to IV4E was detected with digoxigenin (DIG) labeled TNF. This assay could detect down to 300 pg/ml of soluble p55, which represents an 8-10-fold increase in sensitivity compared to earlier developed immunoassays. The assay was specific for soluble p55 TNFR present in serum and cell culture supernatants, since addition of excess unlabeled TNF together with DIG labeled TNF inhibited the signal. TNF concentrations up to 10 ng/ml in the TNFR sample did not affect the assay, indicating that TNFRs can be measured in samples containing TNF. The new immunoassay was used to study the mechanisms underlying the release of soluble p55 TNFR from U937 cells stimulated with TPA. The TPA induced release of soluble p55 TNFR from U937 cells occurred in two phases. First, a rapid increase of soluble p55 was observed after the addition of TPA. Later, the release of p55 occurred at a slower rate, and this release was inhibited by known inhibitors of protein synthesis and intracellular transport. Addition of TPA increased the p55 mRNA expression in U937 cells. The results suggest that TPA induces both release and new synthesis of p55 in U937 cells.

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats.

This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0.13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18- and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18- and 26-month-old rats from basal values of 4.3+/-0.8, 4.7+/-0.5 and 5.6+/-1.0 ng/ml (means+/-s.e.m.) respectively, rose to 11.9+/-1.7, 29.1+/-5.5 and 27.9+/-2.7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-month-old animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3- and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values. Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups. In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance.

Age-dependent reduction in GLUT-2 levels is correlated with the impairment of the insulin secretory response in isolated islets of Sprague-Dawley rats.

In this study we have investigated the insulin secretory response to glucose and other secretagogues (2-ketoisocaproate, 3-isobutyl-1-methyl-xanthine and arginine) of pancreatic islets isolated from Sprague-Dawley rats of various ages (from 2 to 28 months). Our results showed a significant decline in the glucose-stimulated insulin secretion, starting at 12 months of age. On the other hand, the response to non-glucose secretagogues (and mainly to 2-ketoisocaproate) was less impaired with advancing age than that to glucose. We also observed a progressive age-related decline of protein levels of the glucose transporter GLUT-2 in pancreatic islets, which was temporally concomitant and quantitatively comparable with the beta-cell alteration in glucose responsiveness (-40/50%). Finally, we observed a significant increase of the islets insulin content in older rats with respect to younger animals. We conclude that in the islet of older rats the impaired capability to respond to glucose could be dependent, at least in part, on the age-dependent reduction in GLUT-2 and could be compensated by mechanisms including a preserved responsiveness to non-glucose secretagogues and/or the development of islet hypertrophy.

Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment.

OBJECTIVE: To explore the adaptive response of the endocrine pancreas in vivo and in vitro and the possible beneficial effect of the insulino-mimetic agent vanadyl sulfate (VOSO(4)), using glucocorticoid treatment to increase insulin resistance, in aging rats. DESIGN AND METHODS: Dexamethasone (Dex) (0.13 mg/kg b.w.) was administered daily for 13 days to 3- and 18-month old Sprague-Dawley rats and oral VOSO(4) was given from the 5th day. Plasma glucose, insulin and free fatty acids (FFA) concentrations were measured during these treatments and the insulin secretory response of the isolated perfused pancreas was assessed at the end of the experiment. RESULTS AND CONCLUSIONS: In both young and aging rats, particularly in the latter, hyperinsulinemia and increased in vitro insulin responsiveness to glucose were observed in response to Dex treatment, concomitant with an increase in plasma FFA concentrations. Thus, in glucocorticoid-treated animals, the beta-cell adaptive response occurred in both age groups and could possibly be mediated by increased circulating FFA; however, it was insufficient to prevent hyperglycemia in 60% of aging animals. Oral VOSO(4) administration failed to correct Dex-induced alterations in glucose and lipid metabolism, although it influenced in vitro beta-cell responsiveness to stimuli in aging rats.

Protein glycation in the aging male Sprague-Dawley rat: effects of antiaging diet restrictions.

Protein glycation and accumulation of advanced glycosylated end-products (AGEs) are supposed to play an important role in the process of aging. Dietary restriction increases life span and delays the onset of most age-associated diseases. Age-dependent changes in glucose homeostasis and glycated plasma proteins and hemoglobin were determined, and AGEs formation was measured as fluorescence in skin and aortic collagens in male Sprague-Dawley rats fed ad libitum or subjected to every-other-day feeding or 40% food restriction. In aging control rats, skin and aortic collagen-linked fluorescence increased with a similar exponential curve (aortic value being always higher), whereas glycated plasma protein and hemoglobin decreased slightly. Dietary restrictions decreased glycated plasma proteins and fluorescent products in skin collagen of younger but not older rats, and did not affect glycated hemoglobin or aortic collagen fluorescence. In conclusion, our data indicate that age-related changes in glucose homeostasis do not play a substantial role in aging; and collagen-linked fluorescence increases significantly during aging, but it may not be sensitive to dietary intervention.

The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets.

This study intended to test the hypothesis that intracellular lipolysis in the pancreatic beta cells is implicated in the regulation of insulin secretion stimulated by nutrient secretagogues or cyclic adenosine monophosphate (cAMP) agonists. Indeed, although lipid signaling molecules were repeatedly reported to influence beta-cell function, the contribution of intracellular triglycerides to the generation of these molecules has remained elusive. Thus, we have studied insulin secretion of isolated rat pancreatic islets in response to various secretagogues in the presence or absence of 3,5-dimethylpyrazole (DMP), a water-soluble and highly effective antilipolytic agent, as previously shown in vivo. In vitro exposure of islets to DMP resulted in an inhibition (by approximately 50%) of the insulin release stimulated not only by high glucose, but also by another nutrient secretagogue, 2-ketoisocaproate, as well as the cAMP agonists 3-isobutyl-1-methylxanthine and glucagon. The inhibitory effect of DMP, which was not due to alteration of islet glucose oxidation, could be reversed upon addition of sn-1,2-dioctanoylglycerol, a synthetic diglyceride, which activates protein kinase C. The results provide direct pharmacologic evidence supporting the concept that endogenous beta-cell lipolysis plays an important role in the generation of lipid signaling molecules involved in the control of insulin secretion in response to both fuel stimuli and cAMP agonists.

Verapamil acute administration: a new dynamic test in hyperprolactinemic states.

We studied the effect of acute administration of the calcium-channel blocker verapamil (VER) in 27 patients with tumoral hyperprolactinemia ([THPRL] prolactinomas and pseudoprolactinomas). We also studied the effect of VER in seven patients with idiopathic hyperprolactinemia (IHPRL) and a small group of patients with normal prolactin (PRL) levels and minimal incidental anomalies shown by magnetic resonance imaging (MRI). The study was performed on 2 separate days: on the first day, all subjects received VER, and on the second they received placebo. Acute administration of VER evoked a remarkable increase in serum PRL in IHPRL (as in normal healthy subjects used as controls), but no response was shown in THPRL, with no overlap between the two conditions. Acute administration of VER stimulated PRL secretion in patients with minimal incidental lesions shown by MRI; however, this increase was smaller in patients whose PRL level consistently reached the upper-normal limit. Although the meaning of such minimal anomalies shown by MRI is unknown, this could suggest that the test is precociously altered. To further elucidate the action of VER on lactotropes, we investigated the effect of VER given intravenously (IV) and compared different oral formulations in healthy subjects. Our data show that the VER test is effective in distinguishing between THPRL and IHPRL, but unfortunately, like other tests, it is not able to individualize patients in whom THPRL is the result of diminished dopaminergic tone (pseudoprolactinoma). From a pathophysiological point of view, calcium influx would appear less important in PRL regulation in chronic disorders of PRL secretion. VER given IV did not stimulate PRL release in normal subjects. This suggests that IV administration could produce a peak with an inadequate duration or that oral formulations may act also by metabolites formed on first-pass metabolism in the liver.

Effects of low-dose VOSO(4) on age-related changes in glucose homeostasis in rats.

The effects of low doses of vanadyl sulfate (0.2 mg/ml in the drinking water) on the age-related impairment of glucose homeostasis in Sprague-Dawley rats were investigated. VOSO(4) administration was initiated in 5-month-old animals and lasted 3 months. Thus, in 8-month-old rats, we investigated glucose metabolism in vivo and insulin secretory function in vitro. Results showed that VOSO(4) allowed the disposal of an oral glucose load at lower insulin levels than in age-matched controls. No significant changes were found in muscle glucose transporter (GLUT-4) levels or in glycogen content upon VOSO(4) treatment. Islets isolated from VOSO(4)-treated rats released less insulin than control islets, but showed a better preserved sensitivity to secretagogues, in terms of incremental release over basal release, secretory efficiency, and maintenance of the priming effect of glucose. In conclusion, chronic low-dose VOSO(4) treatment facilitates insulin action by a mechanism independent of muscle GLUT-4 levels and helps preserve the appropriate sensitivity of beta cells to stimuli, thereby preventing age-dependent functional alterations.

Impairment of the priming effect of glucose on insulin secretion from isolated islets of aging rats.

The time-dependent potentiation (TDP) of insulin release or priming effect exerted by glucose was evaluated in the islets of Langerhans of mature and old rats. Islets isolated from 12- and 26-month-old male Sprague-Dawley rats and incubated for two consecutive 60-min periods in the presence of various stimulating agents were unable to enhance their insulin responsiveness significantly during the second incubation period and showed other abnormalities in their sensitivity to secretagogues compared with islets from 3-month-old animals. The priming action of glucose plus arginine or isobutylmethylxanthine (IBMX) was not observed in islets from 12-month-old rats, but surprisingly, islets from senescent rats showed a restoration of the beta-cell memory in the presence of IBMX. Interestingly, the islets isolated from 2-month-old animals previously exposed to an intravenous glucose load in vivo released approximately twice as much insulin as the islets taken from fed rats not subjected to the load. This potentiation exerted by the intravenous glucose administration was reduced but not abolished in the islets of glucose-intolerant, 12-month-old rats. In conclusion, the glucose TDP of insulin secretion is impaired in islets of mature and old rats, confirming an early loss of sensitivity of beta-cells to secretagogues during aging.

The regulation of liver protein degradation by aminoacids in vivo. Effects of glutamine and leucine.

The effects in vivo of the two major in vitro regulatory aminoacids, leucine and glutamine, on liver protein degradation were explored in male young adult Sprague Dawley rats. Protein degradation was stimulated by the injection of the antilipolytic drug 3,5 dimethylpyrazole (DMP), which rises glucagon and lowers insulin plasma levels. At the appropriate time-points (20 and 40 min) after the injection of DMP, glutamine or leucine (12.5 mg/kg b.w.) were injected intraperitoneally. The rate of liver protein breakdown was evaluated 60 min after the injection of DMP on the basis of the release of valine into the perfusate during a short term single pass liver perfusion. The aminoacid was assayed by an HPLC procedure. Results show that the administration of glutamine inhibited the DMP-induced increase in the rate of valine release from the perfused liver whereas the administration of leucine did not; neither of the aminoacids appeared to have any effect on the metabolic or endocrine changes that are required for the induction of liver autophagy and protein breakdown by DMP. It is concluded that the aminoacid glutamine has a powerful action on the in vivo regulation of liver protein breakdown, which is not apparent with leucine.

Exploring the mechanisms of in vivo regulation of liver protein breakdown in the rat by the use of the new antilipolytic-agent model.

In this study, we explored the changes in the rate of protein degradation in liver cells in vivo, using a method based on the physiological stimulation of liver autophagy. Male albino rats 1, 2, 6, 12 and 24 months old were fasted overnight, and then received an injection of the antilipolytic agent 3,5-dimethylpyrazole (DMP) to evoke a sudden shortage of lipid fuel. A comparison was made with the in vivo effects of glucagon by giving the 2-month-old group an intraperitoneal injection of this hormone. Samples of liver were taken after 0, 15, 20, 30, 60 and 150 min and processed for electron microscopy, and groups of rats were subjected to short-term single pass liver perfusion. Results show that in the younger age-groups, the DMP stimulation of liver autophagy and amino acid release is highly significant, and compares favourably with the glucagon model of induction of the autophagic process. With older rats, an age-related longer time-lag of the autophagic response and a decrease in the effect of DMP were observed. In conclusion, hormones may activate autophagy, whereas levels of plasma amino acids may tune down the process to adjust the availability of the substrate to tissue needs.

Observation of two-source interference in the photoproduction reaction AuAu --> AuAurho0.

In ultraperipheral relativistic heavy-ion collisions, a photon from the electromagnetic field of one nucleus can fluctuate to a quark-antiquark pair and scatter from the other nucleus, emerging as a rho{0}. The rho{0} production occurs in two well-separated (median impact parameters of 20 and 40 F for the cases considered here) nuclei, so the system forms a two-source interferometer. At low transverse momenta, the two amplitudes interfere destructively, suppressing rho{0} production. Since the rho{0} decays before the production amplitudes from the two sources can overlap, the two-pion system can only be described with an entangled nonlocal wave function, and is thus an example of the Einstein-Podolsky-Rosen paradox. We observe this suppression in 200 GeV per nucleon-pair gold-gold collisions. The interference is 87%+/-5%(stat.)+/-8%(syst.) of the expected level. This translates into a limit on decoherence due to wave function collapse or other factors of 23% at the 90% confidence level.

K/pi Fluctuations at relativistic energies.

We report K/pi fluctuations from Au + Au collisions at sqrt[s(NN)]= 19.6, 62.4, 130, and 200 GeV using the STAR detector at the Relativistic Heavy Ion Collider. K/pi fluctuations in central collisions show little dependence on incident energy and are on the same order as those from NA49 at the Super Proton Synchrotron in central Pb + Pb collisions at sqrt[s(NN)]=12.3 and 17.3 GeV. We report results for the collision centrality dependence of K/pi fluctuations and results for charge-separated fluctuations. We observe that the K/pi fluctuations scale with the charged particle multiplicity density.

Indications of conical emission of charged hadrons at the BNL relativistic heavy ion collider.

Three-particle azimuthal correlation measurements with a high transverse momentum trigger particle are reported for pp, d+Au, and Au+Au collisions at sqrt[s_{NN}]=200 GeV by the STAR experiment. Dijet structures are observed in pp, d+Au and peripheral Au+Au collisions. An additional structure is observed in central Au+Au data, signaling conical emission of correlated charged hadrons. The conical emission angle is found to be theta=1.37+/-0.02(stat)-0.07+0.06(syst), independent of p_{ perpendicular}.

Longitudinal double-spin asymmetry for inclusive jet production in p[over -->] + p[over -->] collisions at sqrt[s]=200 GeV.

We report a new STAR measurement of the longitudinal double-spin asymmetry A(LL) for inclusive jet production at midrapidity in polarized p + p collisions at a center-of-mass energy of sqrt[s]=200 GeV. The data, which cover jet transverse momenta 5