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author:("mers, H.")
1.  The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial 
BMC Women's Health  2015;15:103.
A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection.
We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months.
The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation.
This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection.
Trial registration
Dutch Trial Register NTR3269. Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030
PMCID: PMC4642644  PMID: 26563197
Niche; Caesarean section; Scar defect; Abnormal uterine bleeding; Postmenstrual spotting; Hysteroscopic resection
2.  Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells 
British Journal of Pharmacology  2007;151(7):1041-1048.
Background and purpose:
We investigated expression of cannabinoid receptors and the effects of the endogenous cannabinoid virodhamine and the synthetic agonist CP55,940 on cAMP accumulation and interleukin-8 (IL-8) release in human bronchial epithelial cells.
Experimental approach:
Human bronchial epithelial (16HBE14o-) cells were used. Total mRNA was isolated and cannabinoid receptor mRNAs were detected by RT-PCR. Expression of CB1 and CB2 receptor proteins was detected with Western blotting using receptor-specific antibodies. cAMP accumulation was measured by competitive radioligand binding assay. IL-8 release was measured by ELISA.
Key results:
CB1 and CB2 receptor mRNAs and proteins were found. Both agonists concentration-dependently decreased forskolin-induced cAMP accumulation. This effect was inhibited by the CB2 receptor antagonist SR144528, and was sensitive to Pertussis toxin (PTX), suggesting the involvement of CB2 receptors and Gi/o-proteins. Cell pretreatment with PTX unmasked a stimulatory component, which was blocked by the CB1 receptor antagonist SR141716A. CB2 receptor-mediated inhibition of cAMP production by virodhamine and CP55,940 was paralleled by inhibition of tumor necrosis factor-α (TNF-α) induced IL-8 release. This inhibition was insensitive to SR141716A. In the absence of agonist, SR144528 by itself reduced TNF-α induced IL-8 release.
Conclusions and implications:
Our results show for the first time that 16HBE14o− cells respond to virodhamine and CP55,940. CB1 and CB2 receptor subtypes mediated activation and inhibition of adenylyl cyclase, respectively. Stimulation of the dominant CB2 receptor signalling pathway diminished cAMP accumulation and TNF-α-induced IL-8 release. These observations may imply that cannabinoids exert anti-inflammatory properties in airways by modulating cytokine release.
PMCID: PMC2042924  PMID: 17558435
cannabinoids; virodhamine; CP55,940; human bronchial epithelium; interleukin-8; cAMP; tumour necrosis factor-α
3.  Insulin induces airway smooth muscle contraction 
British Journal of Pharmacology  2006;150(2):136-142.
Background and purpose:
Recently, the use of inhaled insulin formulations for the treatment of type I and type II diabetes has been approved in Europe and in the United States. For regular use, it is critical that airway function remains unimpaired in response to insulin exposure.
Experimental approach:
We investigated the effects of insulin on airway smooth muscle (ASM) contraction and contractile prostaglandin (PG) production, using guinea-pig open-ring tracheal smooth muscle preparations.
Key results:
It was found that insulin (1 nM-1 μM) induced a concentration-dependent contraction that was insensitive to epithelium removal. These sustained contractions were susceptible to inhibitors of cyclooxygenase (indomethacin, 3 μM), Rho-kinase (Y-27632, 1 μM) and p42/44 MAP kinase (PD-98059, 30 μM and U-0126, 3 μM), but not of PI-3-kinase (LY-294002,10 μM). In addition, insulin significantly increased PGF2α-production which was inhibited by indomethacin, but not Y-27632. Moreover, the FP-receptor antagonist AL-8810 (10 μM) and the EP1-receptor antagonist AH-6809 (10 μM) strongly reduced insulin-induced contractions, supporting a pivotal role for contractile prostaglandins.
Conclusions and implications:
Collectively, the results show that insulin induces guinea-pig ASM contraction presumably through the production of contractile prostaglandins, which in turn are dependent on Rho-kinase for their contractile effects. The data suggest that administration of insulin as an aerosol could result in some acute adverse effects on ASM function.
PMCID: PMC2042899  PMID: 17160007
insulin; contraction; airway smooth muscle; Rho-kinase; guinea-pig; prostaglandins
4.  ß2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells 
Thorax  2002;57(1):61-66.
Background: The ß2 adrenoceptor and its 5' untranslated region contain a number of genetic variants. The aim of this study was to investigate the potential for genetic variation at this locus to influence the expression of ß2 adrenoceptors on circulating peripheral blood mononuclear cells (PBMCs).
Methods: Genotype was determined in 96 individuals with asthma for four polymorphisms at the ß2 adrenoceptor locus. ß2 adrenoceptor binding and cyclic AMP responses to isoprenaline in PBMCs were determined and the relationship between genotype/haplotype and ß2 adrenoceptor expression and response to isoprenaline examined.
Results: ß2 adrenoceptor promoter polymorphisms were found to be common in white subjects. Strong linkage disequilibrium exists across this locus, resulting in the occurrence of several common haplotypes. No single polymorphism or haplotype was correlated with the level of ß2 adrenoceptor expression or cyclic AMP responses to isoprenaline in vitro.
Conclusion: ß2 adrenoceptor polymorphisms, when considered in isolation or by extended haplotypes, do not determine the basal level of expression or coupling of ß2 adrenoceptors in PBMCs from asthmatic subjects.
PMCID: PMC1746184  PMID: 11809992
5.  Inflammatory cell distribution in guinea pig airways and its relationship to airway reactivity. 
Mediators of Inflammation  2001;10(3):143-154.
Although airway inflammation and airway hyperreactivity are observed after allergen inhalation both in allergic humans and animals, little is known about the mechanisms by which inflammatory cells can contribute to allergen-induced airway hyperreactivity. To understand how inflammatory cell infiltration can contribute to airway hyperreactivity, the location of these cells within the airways may be crucial Using a guinea pig model of acute allergic asthma, we investigated the inflammatory cell infiltration in different airway compartments at 6 and 24 h (i.e. after the early and the late asthmatic reaction, respectively) after allergen or saline challenge in relation to changes in airway reactivity (AR) to histamine. At 6 h after allergen challenge, a threefold (p < 0.01) increase in the AR to histamine was observed. At 24 h after challenge, the AR to histamine was lower, but still significantly enhanced (1.6-fold, p < 0.05). Adventitial eosinophil and neutrophil numbers in both bronchi and bronchioli were significantly increased at 6 h post-allergen provocation as compared with saline (p < 0.01 for all), while there was a strong tendency to enhanced eosinophils in the bronchial submucosa at this time point (p = 0.08). At 24h after allergen challenge, the eosinophilic and neutrophilic cell infiltration was reduced. CD3+ T lymphocytes were increased in the adventitial compartment of the large airways (p < 0.05) and in the parenchyma (p < 0.05) at 24h post-allergen, while numbers of CD8+ cells did not differ from saline treatment at any time point post-provocation. The results indicate that, after allergen provocation, inflammatory cell numbers in the airways are mainly elevated in the adventitial compartment. The adventitial inflammation could be important for the development of allergen-induced airway hyperreactivity.
PMCID: PMC1781701  PMID: 11545251
6.  Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study. 
British Journal of Pharmacology  1996;119(6):1109-1116.
1. Using a guinea-pig model of allergic asthma, we investigated the role of nitric oxide (NO) in allergen-induced airway hyperreactivity after the early asthmatic reaction, by examining the effects of the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on the responsiveness to methacholine and histamine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge. 2. All animals developed airway hyperreactivity to inhaled histamine at 6 h after ovalbumin challenge, with a mean 3.11 +/- 0.45 fold increase in sensitivity to the agonist (P < 0.001). 3. In perfused tracheal preparations from the ovalbumin-challenged guinea-pigs, the maximal responses (Emax) to methacholine and histamine were significantly enhanced compared to controls, both after intraluminal (IL) and extraluminal (EL) administration of the contractile agonists. In addition, a small but significant increase in the pD2 (-log10 EC50) for IL and EL methacholine and for IL histamine was observed. As a consequence, the delta pD2 (EL-IL) for histamine was slightly decreased from 1.67 +/- 0.13 to 1.23 +/- 0.14 (P < 0.05). However, the delta pD2 for methacholine was unchanged (1.85 +/- 0.11 and 1.77 +/- 0.12, respectively; NS). 4. Incubation of control tracheae with 100 microM L-NAME (IL) significantly enhanced the Emax for both IL and EL methacholine and histamine to approximately the same degree as observed after ovalbumin challenge, with no effect on the pD2 and delta pD2 for both agonists. On the contrary, L-NAME had no effect on Emax and pD2 values of tracheal preparations from ovalbumin-challenged guinea-pigs. 5. L-NAME (10 microM-1 mM) had no effect on methacholine-induced contraction of isolated tracheal strip preparations obtained from control animals, indicating that L-NAME has no antimuscarinic effect on tracheal smooth muscle. 6. Histological examination of the intact tracheal preparations indicated epithelial and subepithelial infiltration of eosinophils after ovalbumin challenge. However, no apparent damage of the airway epithelium was observed in these preparations. 7. The results indicate that a deficiency of NO contributes to allergen-induced airway hyperreactivity after the early asthmatic reaction and that this deficiency appears not to be due to epithelial shedding.
PMCID: PMC1915910  PMID: 8937712
7.  Modulation of agonist-induced phosphoinositide metabolism, Ca2+ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms. 
British Journal of Pharmacology  1996;117(3):419-426.
1. The effects of increased cellular cyclic AMP levels induced by isoprenaline, forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cyclic AMP) on phosphoinositide metabolism and changes in intracellular Ca2+ elicited by methacholine and histamine were examined in bovine isolated tracheal smooth muscle (BTSM) cells. 2. Isoprenaline (pD2 (-log10 EC50) = 6.32 +/- 0.24) and forskolin (pD2 = 5.6 +/- 0.05) enhanced cyclic AMP levels in a concentration-dependent fashion in these cells, while methacholine (pD2 = 5.64 +/- 0.12) and histamine (pD2 = 4.90 +/- 0.04) caused a concentration-related increase in [3H]-inositol phosphates (IP) accumulation in the presence of 10 mM LiCl. 3. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 mM) did not affect the IP accumulation induced by methacholine, but significantly reduced the maximal IP production by histamine (1 mM). However, the effect of isoprenaline was small (15.0 +/- 0.6% inhibition) and insignificant at histamine concentrations between 0.1 and 100 microM. 4. Both methacholine and histamine induced a fast (max. in 0.5-2 s) and transient increase of intracellular Ca2+ concentration ([Ca2+]i) followed by a sustained phase lasting several minutes. EGTA (5 mM) attenuated the sustained phase, indicating that this phase depends on extracellular Ca2+. 5. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 microM) significantly attenuated both the Ca(2+)-transient and the sustained phase generated at equipotent IP producing concentrations of 1 microM methacholine and 100 microM histamine (approx. 40% of maximal methacholine-induced IP response), but did not affect changes in [Ca2+]i induced by 100 microM methacholine (95.2 +/- 3.5% of maximal methacholine-induced IP response). 6. Significant correlations were found between the isoprenaline-induced inhibition of BTSM contraction and inhibition of Ca2+ mobilization or influx induced by methacholine and histamine, that were similar for each contractile agonist. 7. These data indicate that (a) cyclic AMP-dependent inhibition of Ca2+ mobilization in BTSM cells is not primarily caused by attenuation of IP production, suggesting that cyclic AMP induced protein kinase A (PKA) activation is effective at a different level in the [Ca2+]i homeostasis, (b) that attenuation of intracellular Ca2+ concentration plays a major role in beta-adrenoceptor-mediated relaxation of methacholine- and histamine-induced airway smooth muscle contraction, and (c) that the relative resistance of the muscarinic agonist-induced contraction to beta-adrenoceptor agonists, especially at (supra) maximal contractile concentrations is largely determined by its higher potency in inducing intracellular Ca2+ changes.
PMCID: PMC1909321  PMID: 8821529
8.  No evidence for a role of muscarinic M2 receptors in functional antagonism in bovine trachea. 
British Journal of Pharmacology  1995;115(4):665-671.
1. The functional antagonism between methacholine- or histamine-induced contraction and beta-adrenoceptor-mediated relaxation was evaluated in bovine tracheal smooth muscle in vitro. In addition, the putative contribution of muscarinic M2 receptors mediating inhibition of beta-adrenoceptor-induced biochemical responses to this functional antagonism was investigated with the selective muscarinic antagonists, pirenzepine (M1 over M2), AF-DX 116 and gallamine (M2 over M3), and hexahydrosiladiphenidol (M3 over M2). 2. By use of isotonic tension measurement, contractions were induced with various concentrations of methacholine or histamine, and isoprenaline concentration-relaxation curves were obtained in the absence or presence of the muscarinic antagonists. Antagonist concentrations were chosen so as to produce selective blockade of M2 receptors (AF-DX 116 0.1 microM, gallamine 30 microM), or half-maximal blockade of M3 receptors (pirenzepine 0.1 microM, AF-DX 116 0.5 microM, hexahydrosiladiphenidol 0.03 microM). Since these latter antagonist concentrations mimicked KB values towards bovine tracheal smooth muscle M3 receptors, antagonist-induced decreases in contractile tone were compensated for by doubling the agonist concentration. 3. It was found that isoprenaline-induced relaxation of bovine tracheal smooth muscle preparations was dependent on the nature and the concentration of the contractile agonist used. Thus, isoprenaline pD2 (-log EC50) values were decreased 3.7 log units as a result of increasing cholinergic tone from 22 to 106%, and 2.4 log units by increasing histamine tone over a similar range. Furthermore, maximal relaxability of cholinergic tone decreased gradually from 100% at low to only 1.3% at supramaximal contraction levels, whereas with histamine almost complete relaxation was maintained at all concentrations applied.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1908503  PMID: 7582488
9.  Contribution of a cholinergic reflex mechanism to allergen-induced bronchial hyperreactivity in permanently instrumented, unrestrained guinea-pigs. 
British Journal of Pharmacology  1995;114(2):414-418.
1. In conscious, permanently instrumented, unrestrained, ovalbumin-sensitized guinea-pigs the development of allergen-induced bronchial hyperreactivity to histamine- and methacholine-inhalation was investigated after the early as well as after the late asthmatic response. 2. The allergen-induced increase in bronchial reactivity to histamine was significantly higher than to methacholine. 3. The muscarinic receptor antagonist, ipratropium bromide (1.0 mM, 3 min inhalation), blocked methacholine-induced bronchoconstriction and caused a significant 1.7 fold inhibition of the histamine-induced bronchoconstriction of control animals. 4. A lower dose of ipratropium bromide (0.1 mM, 3 min inhalation) had no significant effect on histamine-induced bronchoconstriction in control animals, but significantly reduced the allergen-induced increase in bronchial reactivity to histamine between the early and late asthmatic response. At 1.0 mM ipratropium bromide, no further reduction was observed. 5. These results clearly indicate that an exaggerated cholinergic reflex mechanism contributes to allergen-induced bronchial hyperreactivity to histamine.
PMCID: PMC1510260  PMID: 7881742
10.  Influence of sensitization and allergen provocation procedures on the development of allergen-induced bronchial hyperreactivity in conscious, unrestrained guinea-pigs 
Mediators of Inflammation  1995;4(2):149-156.
The effects of different sensitization and allergen provocation regimens on the development of allergen-induced bronchial hyperreactivity (BHR) to histamine were investigated in conscious, unrestrained guinea-pigs. Similar early and late phase asthmatic reactions, BHR for inhaled histamine after the early (6 h) as well as after the late reaction (24 h), and airway inflammation were observed after a single allergen provocation in animals sensitized to produce mainly IgG or IgE antibodies, respectively. Repeating the allergen provocation in the IgE-sensitized animals after 7 days, using identical provocation conditions, resulted in a similar development of BHR to histamine inhalation. Repetition of the allergen provocation during 4 subsequent days resulted in a decreased development of BHR after each provocation, despite a significant increase in the allergen provocation dose necessary to obtain similar airway obstruction. The number of inflammatory cells in the bronchoalveolar lavage was not significantly changed after repeated provocation, when compared with a single allergen provocation. Finally, we investigated allergen-induced bronchial hyperreactivity by repetition of the sensitization procedure at day 7 and 14 (booster), followed by repeated allergen provocation twice a week for 5 weeks. Surprisingly, no BHR to histamine could be observed after either provocation, while the number of inflammatory cells in the bronchoalveolar lavage fluid after 5 weeks was enhanced compared with controls. These data indicate that both IgE and IgG sensitized guinea-pigs may develop bronchial hyperreactivity after a single allergen provocation. Repeated allergen exposure of IgE sensitized animals causes a gradual fading of the induced hyperreactivity despite the on-going presence of inflammatory cells in the airways, indicating a mechanism of reduced cellular activation.
PMCID: PMC2365622  PMID: 18475633
11.  Characterization of presynaptic vascular muscarinic receptors inhibiting endogenous noradrenaline overflow in the portal vein of the freely moving rat. 
British Journal of Pharmacology  1990;99(2):223-226.
1. In the portal vein of permanently cannulated, freely moving, unanaesthetized rats, methacholine (MCh) is able to inhibit the electrically-evoked endogenous noradrenaline (NA) overflow. This inhibition is mediated by presynaptic inhibitory muscarinic heteroreceptors. 2. By use of pirenzepine, 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) and AF-DX 116 as M1-, M3-, and M2-selective antagonists respectively, the MCh (0.1 microM)-induced inhibition of the electrically-evoked NA overflow could be reversed to the control stimulation value dose-dependently. 3. The potency order of the antagonists was: 4-DAMP greater than AF-DX 116 greater than pirenzepine, pIC50 values being 8.50, 7.96 and 7.01, respectively. 4. From these results it was concluded that the inhibitory presynaptic heteroreceptors in the portal vein of conscious unrestrained rats are of the cardiac M2-subtype.
PMCID: PMC1917397  PMID: 2328391
12.  Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle. 
British Journal of Pharmacology  1990;99(2):293-296.
1. The muscarinic receptor subtype involved in the methacholine-induced enhancement of phosphoinositide metabolism in bovine tracheal smooth muscle was identified by using the M2-selective antagonist AF-DX 116 and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide, in addition to the M1-selective antagonist pirenzepine, in a classical Schild analysis. 2. All the antagonists shifted the methacholine dose-response curve to the right in a parallel and concentration-dependent fashion, yielding Schild plots with slopes not significantly different from unity. The pA2 values (6.94, 6.32 and 8.54 for pirenzepine, AF-DX 116 and 4-DAMP methobromide respectively) indicate that it is the M3 (smooth muscle/glandular), but not the M2 (cardiac) muscarinic receptor subtype, present in this tissue, that mediates phosphoinositide turnover, in accordance with our previous contractile studies. 3. The results provide additional evidence for the involvement of phosphoinositide turnover in the pharmacomechanical coupling between muscarinic receptor stimulation and contraction in (bovine tracheal) smooth muscle.
PMCID: PMC1917404  PMID: 2158372
13.  Laboratory of Physiological Chemistry, State University Groningen, Netherlands. 
Nucleic Acids Research  1979;6(5):1791-1803.
To obtain more information about the arrangement of Hind III restriction fragments in the tRNA-rRNA region of the Neurospora crassa mitochondrial (mt) DNA we have cleaved the mtDNA with Hpa I and Hind II. We could construct additional cleavage maps for these enzymes. Hybridization of rRNAs to Hind II fragments confirmed the existence of an intervening region of about 2,300 basepairs in the 24S rRNA (Hahn et al., Cell, in press). About seven tRNA genes, among which the genes for tRNA1Ser and tRNAMetM, are located in a segment of about 5,000 bp separating the 24S and 17S rRNA genes. Another cluster of 14 tRNA genes is found adjacent to the other end of the 24S gene. The genes for tRNALeu1 and tRNAMetF are located in this cluster.
PMCID: PMC327811  PMID: 156351
14.  Electrocardiogram during cardiac rupture by myocardial infarction 
British Heart Journal  1970;32(2):232-235.
In 100 patients with acute myocardial infarction the electrocardiogram was continuously registered during 72 hours. Nine patients died of ventricular rupture (eight of the left ventricular free wall and one of the ventricular septum). In eight cases death occurred while the electrocardiogram was being recorded. A specific pattern of electrocardiographic changes seems to occur during acute tamponade, i.e. slowing of sinus rhythm followed by nodal rhythm.
PMCID: PMC487308  PMID: 5440517

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