To investigate the risk of clinically relevant bleeding in warfarin-treated patients with or with... more To investigate the risk of clinically relevant bleeding in warfarin-treated patients with or without concomitant treatment with selective serotonin reuptake inhibitors (SSRIs). A cohort study was performed in patients treated with warfarin due to atrial fibrillation. Exposed patients were defined as patients treated with SSRI at any time between January 1999 and September 2005 (n = 117). Unexposed patients without SSRI-treatment were randomly selected and matched for age and sex (1:1). The primary endpoint was hospital admission due to bleeding during the same time period. Bleeding occurred in 17 exposed patients (totally 23 bleedings) and in two unexposed patients (totally two bleedings) (p = 0.0003). A total of 11 bleedings occurred during treatment with the combination of warfarin and SSRI, and 14 during treatment with warfarin only. The total incidences of bleedings per 1000 treatment years were 51.4 (25.7-92.0) and 23.9 (13.1-40.1), respectively, and the unadjusted incidence rate ratio (IRR) 2.15 (0.88-5.11). Cox regression analysis including first bleedings revealed an adjusted hazard ratio of 3.49 (1.37-8.91) for bleeding during treatment with a combination of SSRI and warfarin compared with treatment with warfarin only. Initiation of SSRI therapy was not associated with a change in dose of warfarin or with a change in international normalized ratio (INR) (p = 0.48 and p = 0.31, respectively). Addition of SSRI to warfarin-treated patients may be associated with an increased risk of clinically relevant bleeding. The effect seems not to be associated with a direct influence of SSRI on the anti-coagulant activity of warfarin.
Naunyn-Schmiedeberg's archives of pharmacology, 1997
Neuronal regulation of smooth muscle tone in the female pig urethra has mainly been studied in vi... more Neuronal regulation of smooth muscle tone in the female pig urethra has mainly been studied in vitro using electrical field stimulation (EFS) of nerves. Excitatory control is considered to be exerted by released noradrenaline, whereas inhibitory control is non-adrenergic non-cholinergic (NANC), and mediated by nitric oxide (NO), and an as yet unidentified agent. We investigated the functional and morphological effects of alpha-latrotoxin (alphaLTX), a spider neurotoxin believed to cause massive release of vesicle-stored neurotransmitters, on spontaneously developed urethral smooth muscle tone. The effects were compared to those of EFS and high potassium. In the presence of the NO-synthesis inhibitor N(omega)-nitro-L-arginine (L-NOARG: 0.3 mM) both alphaLTX and EFS evoked contractions. After treatment with scopolamine and phentolamine, no contraction was observed, and under these conditions alphaLTX and EFS induced relaxation. At low frequencies (<12 Hz), the EFS-induced relaxatio...
Journal of the autonomic nervous system, Jan 14, 1997
Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule... more Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule in the central and peripheral nervous systems. In the present study, we have investigated the occurrence of the two isoforms of HO, HO-2 and HO-1 in the canine and feline gastrointestinal tracts, including the small and large intestine and the gastrointestinal sphincters. An abundance of nerve cell bodies that contained immunoreactivity for HO-2 was found in the submucosal and myenteric plexuses. HO-2 immunoreactivity was frequently co-localized with nitric oxide synthase (NOS) or vasoactive intestinal peptide (VIP) immunoreactivities and was also observed in some nerve fibres, certain non-neuronal cells dispersed among smooth muscle bundles, and in vascular endothelium. The antiserum against HO-1 revealed immunoreactivity in nerve cell bodies in the enteric plexuses, in nerve fibres and in non neuronal cells in the smooth muscle layers. Some of the nerve structures were also NOS- or VI...
In the cat lower esophageal sphincter (LES) and esophageal body, nitric oxide synthase (NOS) immu... more In the cat lower esophageal sphincter (LES) and esophageal body, nitric oxide synthase (NOS) immunoreactive nerves were abundant in the circular smooth muscle layer, especially in the LES region. NADPH diaphorase staining showed an identical pattern. The ability to form L-citrulline from L-arginine corresponded roughly to the distribution of NOS. Confocal microscopic analysis indicated colocalization within neurons of vasoactive intestinal peptide (VIP) in 65% of NOS-positive nerves. In LES circular smooth muscle preparations, electrically induced relaxations (single train stimuli) were generally abolished by NG-nitro-L-arginine (L-NNA). Continuous electrical stimulation for 2 min evoked a relaxation in the presence of L-NNA. This relaxation was inhibited by VIP antiserum and followed by a decrease in guanosine 3',5'-cyclic monophosphate, but not by any consistent change in adenosine 3',5'-cyclic monophosphate levels. K+ (124 mM) induced a biphasic relaxation, with L...
Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being th... more Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of activating mutations in TERT regulatory DNA. Although this finding is suggestive of a general mechanism for oncogene activation, this hypothesis remains untested. Here we map somatic mutations in 505 tumor genomes across 14 cancer types and systematically screen for associations between mutations in regulatory regions and RNA-level changes. We identify recurrent promoter mutations in several genes but find that TERT mutations are exceptional in showing a strong and genome-wide significant association with increased expression. Detailed analysis of TERT across cancers shows that the strength of this association is highly variable and is strongest in copy number-stable cancers such as thyroid carcinoma. We additionally propose that TERT promoter mutations control expression of the nearby gene CLPTM1L. Our analysis provides a detailed pan-cancer view of TERT trans...
To study the production of nitric oxide (NO), and the presence of different isoforms of the NO-sy... more To study the production of nitric oxide (NO), and the presence of different isoforms of the NO-synthesising enzyme, NO-synthase (NOS), in the paranasal sinus. Ten patients, undergoing surgery for pituitary adenoma, were examined for the presence of NO gas in the sphenoidal and maxillary sinus. The distribution of different NOS isozymes in mucosal biopsies from sphenoid and maxillary sinus and ethmoidal cells was studied. The mean concentration of NO was 2575 ppb in the sphenoidal sinus and 6792 ppb in the maxillary sinus. Morphological analyses revealed intense NADPH-diaphorase staining throughout the epithelium. Immunoreactivity against NOS2 (inducible NOS) was observed in the apical cell layer but not of the basal layer. NOS1 (neuronal NOS)-immunoreactivity was mainly seen in the subapical part of the epithelium and NOS3 (endothelial NOS)-immunoreactivity was observed only in the most apical part of the epithelium. NO concentration in the sphenoidal sinus is about the same as in t...
The development of novel therapies against melanoma would benefit from individualized tumor model... more The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in ...
The American journal of tropical medicine and hygiene, 2008
Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used... more Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used magnetic resonance imaging (MRI) to monitor alterations in the GI tract of T. cruzi-infected mice, and to assess the role of nitric oxide (NO) in the development of intestinal dilation. Brazil strain-infected C57BL/6 wild-type (WT) mice exhibited dilatation of the intestines by 30 days post-infection. Average intestine lumen diameter increased by 72%. Levels of intestinal NO synthase (NOS) isoforms, NOS2 and NOS3, were elevated in infected WT mice. Inflammation and ganglionitis were observed in all infected mice. Intestinal dilation was observed in infected WT, NOS1, NOS2, and NOS3 null mice. This study demonstrates that MRI is a useful tool to monitor intestinal dilation in living mice and that these alterations may begin during acute infection. Furthermore, our data strongly suggests that NO may not be the sole contributor to intestinal dysfunction resulting from this infection.
Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhib... more Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim. To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; PPI therapy). Fourteen patients (21-69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [-3%, 95% confidence interval (CI), -22;20%], distension (-11%, 95% CI, -28;10%), or electrical current (6%, 95% CI, -10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40-0.79°C), normalizing within 4 h. AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.
To investigate the risk of clinically relevant bleeding in warfarin-treated patients with or with... more To investigate the risk of clinically relevant bleeding in warfarin-treated patients with or without concomitant treatment with selective serotonin reuptake inhibitors (SSRIs). A cohort study was performed in patients treated with warfarin due to atrial fibrillation. Exposed patients were defined as patients treated with SSRI at any time between January 1999 and September 2005 (n = 117). Unexposed patients without SSRI-treatment were randomly selected and matched for age and sex (1:1). The primary endpoint was hospital admission due to bleeding during the same time period. Bleeding occurred in 17 exposed patients (totally 23 bleedings) and in two unexposed patients (totally two bleedings) (p = 0.0003). A total of 11 bleedings occurred during treatment with the combination of warfarin and SSRI, and 14 during treatment with warfarin only. The total incidences of bleedings per 1000 treatment years were 51.4 (25.7-92.0) and 23.9 (13.1-40.1), respectively, and the unadjusted incidence rate ratio (IRR) 2.15 (0.88-5.11). Cox regression analysis including first bleedings revealed an adjusted hazard ratio of 3.49 (1.37-8.91) for bleeding during treatment with a combination of SSRI and warfarin compared with treatment with warfarin only. Initiation of SSRI therapy was not associated with a change in dose of warfarin or with a change in international normalized ratio (INR) (p = 0.48 and p = 0.31, respectively). Addition of SSRI to warfarin-treated patients may be associated with an increased risk of clinically relevant bleeding. The effect seems not to be associated with a direct influence of SSRI on the anti-coagulant activity of warfarin.
Naunyn-Schmiedeberg's archives of pharmacology, 1997
Neuronal regulation of smooth muscle tone in the female pig urethra has mainly been studied in vi... more Neuronal regulation of smooth muscle tone in the female pig urethra has mainly been studied in vitro using electrical field stimulation (EFS) of nerves. Excitatory control is considered to be exerted by released noradrenaline, whereas inhibitory control is non-adrenergic non-cholinergic (NANC), and mediated by nitric oxide (NO), and an as yet unidentified agent. We investigated the functional and morphological effects of alpha-latrotoxin (alphaLTX), a spider neurotoxin believed to cause massive release of vesicle-stored neurotransmitters, on spontaneously developed urethral smooth muscle tone. The effects were compared to those of EFS and high potassium. In the presence of the NO-synthesis inhibitor N(omega)-nitro-L-arginine (L-NOARG: 0.3 mM) both alphaLTX and EFS evoked contractions. After treatment with scopolamine and phentolamine, no contraction was observed, and under these conditions alphaLTX and EFS induced relaxation. At low frequencies (<12 Hz), the EFS-induced relaxatio...
Journal of the autonomic nervous system, Jan 14, 1997
Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule... more Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule in the central and peripheral nervous systems. In the present study, we have investigated the occurrence of the two isoforms of HO, HO-2 and HO-1 in the canine and feline gastrointestinal tracts, including the small and large intestine and the gastrointestinal sphincters. An abundance of nerve cell bodies that contained immunoreactivity for HO-2 was found in the submucosal and myenteric plexuses. HO-2 immunoreactivity was frequently co-localized with nitric oxide synthase (NOS) or vasoactive intestinal peptide (VIP) immunoreactivities and was also observed in some nerve fibres, certain non-neuronal cells dispersed among smooth muscle bundles, and in vascular endothelium. The antiserum against HO-1 revealed immunoreactivity in nerve cell bodies in the enteric plexuses, in nerve fibres and in non neuronal cells in the smooth muscle layers. Some of the nerve structures were also NOS- or VI...
In the cat lower esophageal sphincter (LES) and esophageal body, nitric oxide synthase (NOS) immu... more In the cat lower esophageal sphincter (LES) and esophageal body, nitric oxide synthase (NOS) immunoreactive nerves were abundant in the circular smooth muscle layer, especially in the LES region. NADPH diaphorase staining showed an identical pattern. The ability to form L-citrulline from L-arginine corresponded roughly to the distribution of NOS. Confocal microscopic analysis indicated colocalization within neurons of vasoactive intestinal peptide (VIP) in 65% of NOS-positive nerves. In LES circular smooth muscle preparations, electrically induced relaxations (single train stimuli) were generally abolished by NG-nitro-L-arginine (L-NNA). Continuous electrical stimulation for 2 min evoked a relaxation in the presence of L-NNA. This relaxation was inhibited by VIP antiserum and followed by a decrease in guanosine 3',5'-cyclic monophosphate, but not by any consistent change in adenosine 3',5'-cyclic monophosphate levels. K+ (124 mM) induced a biphasic relaxation, with L...
Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being th... more Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of activating mutations in TERT regulatory DNA. Although this finding is suggestive of a general mechanism for oncogene activation, this hypothesis remains untested. Here we map somatic mutations in 505 tumor genomes across 14 cancer types and systematically screen for associations between mutations in regulatory regions and RNA-level changes. We identify recurrent promoter mutations in several genes but find that TERT mutations are exceptional in showing a strong and genome-wide significant association with increased expression. Detailed analysis of TERT across cancers shows that the strength of this association is highly variable and is strongest in copy number-stable cancers such as thyroid carcinoma. We additionally propose that TERT promoter mutations control expression of the nearby gene CLPTM1L. Our analysis provides a detailed pan-cancer view of TERT trans...
To study the production of nitric oxide (NO), and the presence of different isoforms of the NO-sy... more To study the production of nitric oxide (NO), and the presence of different isoforms of the NO-synthesising enzyme, NO-synthase (NOS), in the paranasal sinus. Ten patients, undergoing surgery for pituitary adenoma, were examined for the presence of NO gas in the sphenoidal and maxillary sinus. The distribution of different NOS isozymes in mucosal biopsies from sphenoid and maxillary sinus and ethmoidal cells was studied. The mean concentration of NO was 2575 ppb in the sphenoidal sinus and 6792 ppb in the maxillary sinus. Morphological analyses revealed intense NADPH-diaphorase staining throughout the epithelium. Immunoreactivity against NOS2 (inducible NOS) was observed in the apical cell layer but not of the basal layer. NOS1 (neuronal NOS)-immunoreactivity was mainly seen in the subapical part of the epithelium and NOS3 (endothelial NOS)-immunoreactivity was observed only in the most apical part of the epithelium. NO concentration in the sphenoidal sinus is about the same as in t...
The development of novel therapies against melanoma would benefit from individualized tumor model... more The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in ...
The American journal of tropical medicine and hygiene, 2008
Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used... more Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used magnetic resonance imaging (MRI) to monitor alterations in the GI tract of T. cruzi-infected mice, and to assess the role of nitric oxide (NO) in the development of intestinal dilation. Brazil strain-infected C57BL/6 wild-type (WT) mice exhibited dilatation of the intestines by 30 days post-infection. Average intestine lumen diameter increased by 72%. Levels of intestinal NO synthase (NOS) isoforms, NOS2 and NOS3, were elevated in infected WT mice. Inflammation and ganglionitis were observed in all infected mice. Intestinal dilation was observed in infected WT, NOS1, NOS2, and NOS3 null mice. This study demonstrates that MRI is a useful tool to monitor intestinal dilation in living mice and that these alterations may begin during acute infection. Furthermore, our data strongly suggests that NO may not be the sole contributor to intestinal dysfunction resulting from this infection.
Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhib... more Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim. To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; PPI therapy). Fourteen patients (21-69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [-3%, 95% confidence interval (CI), -22;20%], distension (-11%, 95% CI, -28;10%), or electrical current (6%, 95% CI, -10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40-0.79°C), normalizing within 4 h. AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.
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