bluuebunny/crossref_metadata_2025_split huggingface dataset:
A ketolide antibiotic, telithromycin, inhibits vascular adrenergic neurotransmission in the rat mesenteric vascular bed
Authors: Hatanaka Y , Zamami Y , Koyama T , Hobara N , Jin X , Kitamura Y , Kawasaki H 
Published: August 2008

Background and purpose:A ketolide antibiotic, telithromycin, has side effects including temporary loss of consciousness in clinical use, but the underlying mechanisms remain unclear. This study investigated the effects of telithromycin on perivascular nerve function in rat mesenteric arteries, in comparison with those of macrolide (erythromycin and clarithromycin) and new quinolone antibiotics (levofloxacin and gatifloxacin).Experimental approach:In vitro, vascular responses and release of noradrenaline induced by periarterial nerve stimulation (PNS) of rat perfused mesenteric vascular beds were measured in the presence of each antibiotic.In vivoblood pressure measurement was performed in Wistar rats.Key results:In mesenteric preparations with resting tone, telithromycin (10 nM–10 μM) markedly inhibited PNS (4–12 Hz)‐induced adrenergic nerve‐ and exogenous noradrenaline‐mediated vasoconstriction, whereas the other antibiotics slightly inhibited PNS‐induced responses without affecting noradrenaline‐induced responses. Telithromycin significantly reduced PNS (12 Hz)‐evoked noradrenaline release in the perfusate. In pre‐constricted preparations with or without endothelium, telithromycin (0.1 nM–10 μM) caused a concentration‐dependent vasodilation. Telithromycin (10 nM) inhibited calcium‐induced vasoconstriction in high KCl and calcium‐free medium. None of the antibiotics used affected PNS (0.5–2 Hz)‐induced calcitonin gene‐related peptide (CGRP) nerve‐ and exogenous CGRP‐mediated vasodilation. Intravenous injection of telithromycin significantly lowered blood pressure in anaesthetized rats.Conclusions and implications:These results suggest that telithromycin causes not only strong inhibition of perivascular adrenergic neurotransmission but also a vasodilator action in mesenteric vascular beds and hypotension. It is thus possible that telithromycin increases visceral blood flow, consequently reducing cerebral blood flow and resulting in a temporary loss of consciousness.British Journal of Pharmacology(2008)155, 826–836; doi:10.1038/bjp.2008.313; published online 11 August 2008
Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety
Authors: Chávez‐Piña A E , Vong L , McKnight W , Dicay M , Zanardo R C O , Ortiz M I , Castañeda‐Hernández G , Wallace J L 
Published: August 2008

Background and purpose:Acemetacin is a non‐steroidal anti‐inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin.Experimental approach:The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B4 and thromboxane B2, on leukocyte‐endothelial adherence in post‐capillary mesenteric venules, and on gastric expression of tumour necrosis factor‐α (TNF‐α) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX‐2 and NOS.Key results:Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF‐α. Pretreatment with L‐nitro‐arginine methyl ester or lumiracoxib increased the severity of indomethacin‐induced gastric damage, but this was not the case with acemetacin.Conclusions and implications:The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte–endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene‐B4 synthesis and TNF‐α expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.British Journal of Pharmacology (2008) 155, 857–864; doi:10.1038/bjp.2008.316; published online 11 August 2008
(Pro3)GIP[mPEG]: novel, long‐acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity‐diabetes (diabesity) therapy
Authors: McClean P L , Irwin N , Hunter K , Gault V A , Flatt P R 
Published: August 2008

Background and purpose:Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline‐3 gastric inhibitory polypeptide ((Pro3)GIP) can reverse or prevent many of the metabolic abnormalities associated with diet‐induced obesity‐diabetes (diabesity). This study has examined the ability of a novel and longer‐acting form of (Pro3)GIP, (Pro3)GIP mini‐polyethylene glycol ((Pro3)GIP[mPEG]), to counter diet‐induced diabesity in mice, using a daily and intermittent dosing regime.Experimental approach:We studied the actions of (Pro3)GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity.Key results:(Pro3)GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro3)GIP[mPEG] inhibited GIP‐induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP‐induced glucose‐lowering action was followed (Pro3)GIP[mPEG] administration, compared with (Pro3)GIP. In contrast with (Pro3)GIP, mice injected once every 3 days for 48 days with (Pro3)GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high‐fat‐fed controls. Daily i.p. injection of (Pro3)GIP, (Pro3)GIP[mPEG] or (Pro3)GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high‐fat controls. Plasma triglycerides were decreased by (Pro3)GIP[mPEG] and (Pro3)GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro3)GIP[mPEG] was also effective over 16 days treatment of genetically obese‐diabetic ob/ob mice.Conclusions and implications:These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro3)GIP[mPEG] as a long‐acting stable GIP receptor antagonist.British Journal of Pharmacology (2008) 155, 690–701; doi:10.1038/bjp.2008.317; published online 11 August 2008
Native profiles of α1A‐adrenoceptor phenotypes in rabbit prostate
Authors: Su T‐H , Morishima S , Suzuki F , Yoshiki H , Anisuzzaman A S M , Tanaka T , Cheng J‐T , Muramatsu I 
Published: August 2008

Background and purpose:α1‐Adrenoceptors in the rabbit prostate have been studied because of their controversial pharmacological profiles in functional and radioligand binding studies. The purpose of the present study is to determine the native profiles of α1‐adrenoceptor phenotypes and to clarify their relationship.Experimental approach:Binding experiments with [3H]‐silodosin and [3H]‐prazosin were performed using intact tissue segments and crude membrane preparations of rabbit prostate and the results were compared with α1‐adrenoceptor‐mediated prostate contraction.Key results:[3H]‐Silodosin at subnanomolar concentrations bound specifically to intact tissue segments of rabbit prostate. However, [3H]‐prazosin at the same range of concentrations failed to bind to α1‐adrenoceptors of intact segments. Binding sites of [3H]‐silodosin in intact segments were composed of α1Lphenotype with low affinities for prazosin (pKi=7.1), 5‐methyurapidil andN‐[2‐(2‐cyclopropylmethoxyphenoxy)ethyl]‐5‐chloro‐α,α‐dimethyl‐1H‐indole‐3‐ethamine hydrochloride (RS‐17053), and α1A‐like phenotype with moderate affinity for prazosin (pKi=8.8) but high affinity for 5‐methyurapidil and RS‐17053. In contrast, both radioligands bound to a single population of α1‐adrenoceptors in the membrane preparations at the same density with a subnanomolar affinity, showing a typical profile of ‘classical’ α1A‐adrenoceptors (pKi for prazosin=9.8). The pharmacological profile of α1‐adrenoceptor‐mediated prostate contraction was in accord with the α1Lphenotype observed by intact segment binding approach.Conclusions and implications:Three distinct phenotypes (α1Land α1A‐like phenotypes in the intact segments and a classical α1Aphenotype in the membranes) with different affinities for prazosin were detected in rabbit prostate. It appears that the three phenotypes are phenotypic subtypes of α1A‐adrenoceptors, but are not genetically different subtypes.British Journal of Pharmacology(2008)155, 906–912; doi:10.1038/bjp.2008.318; published online 11 August 2008
Kallikrein inhibitors limit kinin B2antagonist‐induced progression of oedematous to haemorrhagic pancreatitis in rats
Authors: Griesbacher T , Rainer I , Tiran B , Peskar B A 
Published: August 2008

Background and purpose:Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B2receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors.Experimental approach:Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors α1‐antitrypsin (α1‐AT) and α2‐macroglobulin (α2‐M) were measured.Key results:Haemorrhagic lesions induced by icatibant in caerulein‐induced pancreatitis were associated with a reduction in α1‐AT and α2‐M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished.Conclusions and implications:Reduced oedema formation by B2antagonists prevented influx of endogenous kallikrein inhibitors and led to an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue‐type and plasma‐type kallikrein. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis.British Journal of Pharmacology(2008)155, 865–874; doi:10.1038/bjp.2008.321; published online 11 August 2008
Modulation of the anti‐nociceptive effects of 2‐arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model
Authors: Desroches J , Guindon J , Lambert C , Beaulieu P 
Published: August 2008

Background and purpose:There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2‐arachidonoyl glycerol (2‐AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2‐AG biosynthesis and metabolism. It has been clearly demonstrated that 2‐AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti‐nociceptive effects of the combination of peripherally injected 2‐AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB1(AM251) and CB2(AM630) receptor antagonists.Experimental approach:Mechanical allodynia and thermal hyperalgesia were evaluated in 213 male Wistar rats allocated to 32 different groups. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 μL) 15 min before pain tests.Key results:2‐AG, URB602 and URB597 significantly decreased mechanical allodynia and thermal hyperalgesia with ED50 of 1.6±1.5 and 127±83 μg for 2‐AG and URB602, respectively. These effects were mediated locally and were mostly inhibited by the two cannabinoid antagonists.Conclusions and implications:The combination of the three compounds did not produce any greater anti‐allodynic or anti‐hyperalgesic effects, suggesting that FAAH inhibition could reduce or limit the anti‐nociceptive effects of 2‐AG. Peripheral administration of endocannabinoids or MGL/FAAH inhibitors is a promising analgesic approach requiring further investigation.British Journal of Pharmacology(2008)155, 913–924; doi:10.1038/bjp.2008.322; published online 11 August 2008
‘Entourage’ effects ofN‐palmitoylethanolamide andN‐oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors
Authors: Ho W‐SV , Barrett D A , Randall M D 
Published: August 2008

Background and purpose:The endocannabinoidN‐arachidonoylethanolamide (anandamide) is co‐synthesized with otherN‐acylethanolamides, namelyN‐palmitoylethanolamide (PEA) andN‐oleoylethanolamide (OEA), which have been shown to potentiate anandamide responses (so‐called ‘entourage effects’) in non‐vascular tissues. It remains unclear whether such interactions occur in the circulation.Experimental approach:In rat isolated small mesenteric arteries, the effects of PEA and OEA on relaxation to anandamide and tissue contents of theN‐acylethanolamides were examined under myographic conditions.Key results:Anandamide‐induced relaxation was potentiated by pretreatment with PEA (10 μM) or OEA (1 μM), or in combination. The potentiation by PEA and OEA was endothelium‐independent and abolished by treatment with capsaicin (10 μM), which desensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor system, or by the TRPV1 receptor antagonist,N‐(3‐methoxyphenyl)‐4‐chlorocinnamide (SB366791) (2 μM). It was also observed at molar ratios of anandamide and PEA (or OEA) similar to those found in mesenteric arteries. PEA and inhibition of anandamide hydrolysis by 3′‐carbamoyl‐biphenyl‐3‐yl‐cyclohexylcarbamate (URB597) (1 μM) additively potentiated anandamide responses. On the other hand, PEA and OEA also induced vasorelaxationper se(rank order of potency: anandamide>OEA>PEA), but relaxation to the threeN‐acylethanolamides displayed different sensitivity to treatment with capsaicin, SB366791 and URB597. For example, relaxations to anandamide and OEA, but not PEA, were attenuated by both capsaicin and SB366791.Conclusion and implications:This study shows that PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxationper se, suggesting a function for theN‐acylethanolamides in vascular control.British Journal of Pharmacology(2008)155, 837–846; doi:10.1038/bjp.2008.324; published online 11 August 2008
A single channel for nitrate uptake, nitrite export and nitrite uptake by Escherichia coli NarU and a role for NirC in nitrite export and uptake
Authors: Jia Wenjing , Tovell Nicholas , Clegg Stephanie , Trimmer Mark , Cole Jeffrey 
Published: August 2008

Two related polytopic membrane proteins of the major facilitator family, NarK and NarU, catalyse nitrate uptake, nitrite export and nitrite uptake across the Escherichia coli cytoplasmic membrane by an unknown mechanism. A 12-helix model of NarU was constructed based upon six alkaline phosphatase and β-galactosidase fusions to NarK and the predicted hydropathy for the NarK family. Fifteen residues conserved in the NarK-NarU protein family were substituted by site-directed mutagenesis, including four residues that are essential for nitrate uptake by Aspergillus nidulans: arginines Arg87 and Arg303 in helices 2 and 8, and two glycines in a nitrate signature motif. Despite the wide range of substitutions studied, in no case did mutation result in loss of one biochemical function without simultaneous loss of all other functions. A NarU+ NirC+ strain grew more rapidly and accumulated nitrite more rapidly than the isogenic NarU+ NirC− strain. Only the NirC+ strain consumed nitrite rapidly during the later stages of growth. Under conditions in which the rate of nitrite reduction was limited by the rate of nitrite uptake, NirC+ strains reduced nitrite up to 10 times more rapidly than isogenic NarU+ strains, indicating that both nitrite efflux and nitrite uptake are largely dependent on NirC. Isotope tracer experiments with [15N]nitrate and [14N]nitrite revealed that [15N]nitrite accumulated in the extracellular medium even when there was a net rate of nitrite uptake and reduction. We propose that NarU functions as a single channel for nitrate uptake and nitrite expulsion, either as a nitrate–nitrite antiporter, or more likely as a nitrate/H+ or nitrite/H+ channel.
The splicing factor Prp17 interacts with the U2, U5 and U6 snRNPs and associates with the spliceosome pre- and post-catalysis
Authors: Sapra Aparna K. , Khandelia Piyush , Vijayraghavan Usha 
Published: August 2008

Saccharomyces cerevisiae PRP17-null mutants are temperature-sensitive for growth. In vitro splicing with extracts lacking Prp17 are kinetically slow for the first step of splicing and are arrested for the second step at temperatures greater than 34 °C. In the present study we show that these stalled spliceosomes are compromised for an essential conformational switch that is triggered by Prp16 helicase. These results suggest a plausible mechanistic basis for the second-step arrest in prp17Δ extracts and support a role for Prp17 in conjunction with Prp16. To understand the association of Prp17 with spliceosomes we used a functional epitope-tagged protein in co-immunoprecipitation experiments. Examination of co-precipitated snRNAs (small nuclear RNAs) show that Prp17 interacts with U2, U5 and U6 snRNPs (small nuclear ribonucleoproteins) but it is not a core component of any one snRNP. Prp17 association with in-vitro-assembled spliceosome complexes on actin pre-mRNAs was also investigated. Although the U5 snRNP proteins Prp8 and Snu114 are found in early pre-spliceosomes that contain all five snRNPs, Prp17 is not detectable at this step; however, Prp17 is present in the subsequent pre-catalytic A1 complex, containing unspliced pre-mRNA, formed after the dissociation of U4 snRNP. Thus Prp17 joins the spliceosome prior to both catalytic reactions. Our results indicate continued interactions in catalytic spliceosomes that contain reaction intermediates and in post-splicing complexes containing the lariat intron. These Prp17–spliceosome association analyses provide a biochemical basis for the delayed first step in prp17Δ and explain the previously known multiple genetic interactions between Prp17, factors of the Prp19-complex [NTC (nineteen complex)], functional elements in U2 and U5 snRNAs and other second-step splicing factors.
Robotic retroperitoneal lower para‐aortic lymphadenectomy in cervical carcinoma: First report on the technique used in 5 patients
Authors: VERGOTE IGNACE , POUSEELE BRAM , VAN GORP TOON , VAN ACKER BERNARD , LEUNEN KARIN , CADRON ISABELLE , NEVEN PATRICK , AMANT FREDERIC 
Published: August 2008

AbstractObjective. Retroperitoneal para‐aortic laparoscopic lymphadenectomy is a technically challenging operation. The robotic Da Vinci system might be valuable in this operation due to a steady three‐dimensional visualization, instrumentation with articulating tips, and an adaptive downscaling of the surgeons movements (without tremor). To the best of our knowledge, this is the first report on robotic retroperitoneal para‐aortic lymphadenectomy in patients with gynecologic cancer.Method and results. We report on the technique and operative results of the robotic retroperitoneal lower para‐aortic lymphadenectomy using the Da Vinci Surgical System. Five patients with cervical carcinoma stage IIb‐IIb were included. Technically the procedure was easier to perform than with the classical retroperitoneal laparoscopic approach. However using the Da Vinci Surgical System it is important to tilt the patient slightly to the left to avoid collision between the left arm of the patient and the robotic arms, and to place the endoscopic robotic arm between the 2 arms used for dissection. Finally, we experienced that using a 30° scope is advantageous for the dissection of the paracaval nodes. None of the patients had evidence of para‐aortic metastases on preoperatively staging, including Positron Emission Tomography – Computed Tomography (PET‐CT). One of the patients had positive para‐aortic lymph nodes.Conclusion. Here we report on the surgical technique used in our first 5 patients undergoing retroperitoneal para‐aortic lymphadenectomy using the robotic Da Vinci system. It is important to adapt the surgical technique using the Da Vinci Surgical System compared with the classical laparoscopic technique.
Do pregnant women still smoke? A study of smoking patterns among 261,029 primiparous women in Denmark 1997–2005
Authors: EGEBJERG JENSEN KIRSTEN , JENSEN ALLAN , NØHR BUGGE , KRÜGER KJÆR SUSANNE 
Published: August 2008

AbstractObjective. Describe smoking patterns in pregnancy in Denmark from 1997 to 2005 and make comparisons with the other Nordic countries, and further to analyze the influence of socio‐demographic factors on smoking patterns in pregnancy. Design. Register‐based study. Setting. Denmark. Population. All primiparous women giving birth in Denmark (n = 261,029) in the period 1997–2005. Methods. Information about deliveries, smoking status and characteristics of the women were retrieved from the Danish National Birth Registry. Multiple logistic regression analysis was used to assess the importance of different factors in relation to the risk of smoking in pregnancy. Main outcome measures. Odds Ratios and associated 99% confidence intervals were used to assess the risk of smoking in pregnancy. Results. The prevalence of women who smoked at some point in pregnancy declined significantly from 22% in 1997 to 16% in 2005. However, among women younger than 20 years at delivery, the pregnancy‐related smoking prevalence increased from 37 to 43%. Time trends in smoking patterns were not confounded by socio‐demographic factors. Women living in rural areas and women who did not have a partner had the highest risk of smoking in pregnancy. Conclusions. In this nationwide survey, a significant decline in the prevalence of primiparous women who smoked during pregnancy was observed from 1997 to 2005. Despite of this, pregnancy‐related smoking prevalence in Denmark is still higher than in the other Nordic countries. Furthermore, the proportion of pregnant smokers was highest among young women, and future smoking cessation programs should bring this subgroup of women into focus.