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1.  Everolimus- and sirolimus-eluting stents in patients with and without ST-segment elevation myocardial infarction 
Netherlands Heart Journal  2014;22(4):167-173.
Everolimus-eluting stents (EES) were superior to sirolimus-eluting stents (SES) in a dedicated myocardial infarction trial, a finding that was not observed in trials with low percentages of ST-elevation myocardial infarction (STEMI). Therefore, this study sought to investigate the influence of clinical presentation on outcome after EES and SES implantation.
A pooled population of 1602 randomised patients was formed from XAMI (acute MI trial) and APPENDIX-AMI (all-comer trial). Primary outcome was cardiac mortality, MI and target vessel revascularisation at 2 years. Secondary endpoints included definite/probable stent thrombosis (ST). Adjustment was done using Cox regression.
In total, 902 EES and 700 SES patients were included, of which 44 % STEMI patients (EES 455; SES 257) and 56 % without STEMI (EES 447; SES 443). In the pooled population, EES and SES showed similar outcomes during follow-up. Moreover, no differences in the endpoints were observed after stratification according to presentation. Although a trend toward reduced early definite/probable ST was observed in EES compared with SES in STEMI patients, long-term ST rates were low and comparable.
EES and SES showed a similar outcome during 2-year follow-up, regardless of clinical presentation. Long-term safety was excellent for both devices, despite wide inclusion criteria and a large sub-population of STEMI patients.
PMCID: PMC3954924  PMID: 24522952
Drug-eluting stents; Percutaneous coronary intervention; Coronary artery disease
2.  Brain metastases free survival differs between breast cancer subtypes 
British Journal of Cancer  2012;106(3):440-446.
Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010.
Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test.
Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014).
Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.
PMCID: PMC3273356  PMID: 22233926
advanced breast cancer; brain metastases; carcinomatous meningitis; human epidermal growth factor receptor 2 (HER-2)-positive breast cancer; triple-negative disease
3.  Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) 
Endoscopy  2011;44(1):74-94.
Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.
PMCID: PMC3367502  PMID: 22198778
4.  Epidemiological trends of pre‐malignant gastric lesions: a long‐term nationwide study in the Netherlands 
Gut  2007;56(12):1665-1670.
The pre‐malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer.
To evaluate epidemiological time trends of pre‐malignant gastric lesions in the Netherlands.
Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age–period–cohort models using logistic regression analysis.
In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age–period–cohort models a cohort phenomenon was demonstrated for all categories of pre‐malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM.
The incidence of pre‐malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention.
PMCID: PMC2095713  PMID: 17698860
5.  RESPONSE study: Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists 
Netherlands Heart Journal  2009;17(9):322-328.
Background. Patients with coronary artery disease are at high risk of coronary events and death, but effective secondary prevention can reduce this risk. There is a gap between guidelines on secondary prevention and the implementation of these measures, which could potentially be reduced by nurse led prevention clinics (NLPC).
Objectives. The aim of the current study is to quantify the impact of NLPC on the risk of cardiovascular events in patients with established coronary artery disease.
Methods. A randomised, multicentre clinical trial of NLPC in addition to usual care or usual care alone in post-acute coronary syndrome patients. (Neth Heart J 2009;17:322-8.19949473)
PMCID: PMC2758346  PMID: 19949473
cardiovascular diseases; aetiology; prevention & control; coronary disease; complications; drug therapy; health behaviour; lifestyle; nurse's role; risk factors
6.  A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database 
Archives of Disease in Childhood  2004;89(12):1098-1102.
Aims: To characterise prescribing patterns of antidepressants (ATDs) to children and adolescents aged ⩽18 years in the UK.
Methods: Subjects issued at least one ATD prescription between 1 January 1992 and 31 December 2001 were identified from the UK General Practice Research Database. Prescribing patterns, annual prevalence, morbidity patterns, and time to discontinuation of ATD use were identified.
Results: A total of 24 976 subjects received 93 091 prescriptions; 51 868 (55.7%), 38 429 (41.3%), and 2708 (2.9%) prescriptions were for tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other ATDs respectively. ATD prevalence increased 1.7-fold from 1992 to 2001. TCA prevalence decreased by 30% from 3.6 to 2.5 per 1,000; SSRI prevalence increased 10 times from 0.5 to 4.6 per 1,000. In new ATD users aged ⩽10 years, the most common diagnosis associated with TCA use was nocturnal enuresis (75.1%); in those aged ⩾15 years, it was depression (45.8%). Depression was also associated with SSRI use (69.0%). For new users with depression, the median treatment durations for TCAs and SSRIs were 30 and 58 days respectively. TCA users were more likely to terminate treatment than SSRI users (TCAs v fluoxetine: 1.40, 95% CI 1.32 to 1.47; non-fluoxetine SSRIs v fluoxetine: 1.01, 95% CI 0.96 to 1.07).
Conclusions: SSRIs have gained popularity for the treatment of depression compared with TCAs. TCAs are still used despite their lack of efficacy in prepubertal depression and their moderate effect in adolescents. However, >50% of subjects discontinue treatment after two months, with TCA users stopping earlier than SSRI users.
PMCID: PMC1719765  PMID: 15557040
10.  Corneal sensitivity in patients with leprosy and in controls. 
AIMS--In a quantitative prospective study the corneal sensation in patients with leprosy was compared with age matched controls. METHODS--The patients with leprosy were classified as paucibacillary and multibacillary and were divided in three groups: (1) patients without clinically detectable eye pathology; (2) patients with lagophthalmos, (3) patients with signs of iridocyclitis. The corneal sensitivity was assessed with the Cochet and Bonnet aesthesiometer. RESULTS--There was a significant decrease in corneal sensitivity in multibacillary patients without clinically detectable eye pathology and in patients with lagophthalmos or iritis when compared with controls. A significant correlation between the loss of power of the orbicularis oculi muscle and the degree of corneal sensation loss could not be established. No significant decrease in corneal sensitivity was found in paucibacillary patients without eye pathology compared with the control group. CONCLUSION--The results of this study showed that loss of corneal sensation can occur while there is no clinically detectable eye pathology, at least in multibacillary patients. Regular checkups of the corneal sensation should, therefore, be part of the routine control of leprosy patients. Health education on eye care and early warning signs should be encouraged.
PMCID: PMC505313  PMID: 8534670
11.  Initial and long-term results of coronary angioplasty and coronary bypass surgery in patients of 75 or older. 
British Heart Journal  1993;70(2):122-125.
OBJECTIVE--To evaluate clinical outcome after percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) in patients of 75 or older who underwent either procedure between 1980 and 1987. SUBJECTS--93 patients aged 75-89 with angina pectoris class III-IV (Canadian Cardiovascular Society) who underwent PTCA and 81 patients aged 75-84 with angina class III-IV who underwent CABG. Follow up was 8.2 years in the PTCA group and 8.3 years in the CABG group. MAIN OUTCOME MEASURES--In-hospital complications and survival at follow up. RESULTS--Primary success rate for PTCA was 84% (78/93). Two patients died, two had emergency CABG, three had a myocardial infarction, and one had a cerebrovascular accident. PTCA failed in seven patients (five underwent elective CABG and two were treated conservatively). Median hospital stay was 4.3 days. Primary success rate for CABG was 63% (53/81). Six patients died, two had a cerebrovascular accident, eight had a myocardial infarction, 10 had a rethoracotomy, and four the adult respiratory distress syndrome. Median hospital stay was 14.2 days. In the PTCA group during follow up eight patients died, three had a non-fatal myocardial infarction, two had elective CABG, 10 had repeat PTCA, and four had recurrence of angina. Sixty four patients were free of angina (69%). In the CABG group during follow up eight patients died, one had a non-fatal myocardial infarction, six had PTCA, and three had recurrence of angina. Fifty seven patients were free of angina AP (70%). Actuarial survival after 10 years was 92% for PTCA and 91% for CABG. CONCLUSIONS--PTCA is safe in elderly patients. The complication rate is lower and hospital stay significantly shorter compared with CABG (p < 0.05). Long-term follow up showed no significant difference between PTCA and CABG.
PMCID: PMC1025270  PMID: 8038020
12.  Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities. 
Molecular and Cellular Biology  1992;12(1):82-88.
We have cloned a genomic region of the murine fibroblast growth factor (FGF) receptor 1 (FGFR1) gene that includes three alternative exons for the third immunoglobulinlike domain in the extracellular region of the receptor. The mRNA of one of these splice variants encodes a secreted receptor that lacks transmembrane and cytoplasmic sequences as well as a portion of the third immunoglobulinlike domain. Highest levels of mRNA encoding this variant were found in brain, skeletal muscle, and skin. We expressed this form of FGFR1 in CHO cells and showed that the recombinant secreted protein binds acidic FGF. We also discovered a novel alternative exon in the third immunoglobulinlike domain that encodes part of a transmembrane FGFR1 mRNA. This exon is highly homologous to the corresponding region of the keratinocyte growth factor receptor. Transcripts including this exon were present at highest levels in the skin. We cloned an FGFR1 cDNA which includes this exon and expressed this receptor variant in L6 rat skeletal muscle myoblasts. The new receptor variant had a 50-fold-lower affinity for basic FGF than does the published FGFR1 variant, whereas both forms of receptor bound acidic FGF with high affinity. These results show that the third immunoglobulinlike domain plays an important role in determining the binding specificities for different FGFs. Our data provide the first evidence that differential splicing in the extracellular region of a receptor gene generates receptor variants with different ligand-binding specificities.
PMCID: PMC364071  PMID: 1309595
13.  Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA. 
Journal of Clinical Investigation  1989;84(2):647-655.
Plasminogen activation is catalyzed both by tissue-type-(t-PA) and by urokinase-type plasminogen activator (u-PA). This reaction is controlled by plasminogen activator inhibitor type 1 (PAI-1) that is either present in plasma or bound to fibrin, present in a thrombus. We studied the mechanism of in vitro inhibition of both t-PA and u-PA activity by PAI-1 bound to fibrin. It is shown that activation of latent PAI-1 unmasks a specific fibrin-binding site that is distinct from its reactive site. This reactive site of activated PAI-1 bound to fibrin is fully exposed to form complexes with t-PA and u-PA, that are unable to activate plasminogen. Upon complex formation with either one of the plasminogen activators, PAI-1 apparently undergoes a conformational change and loses its affinity for fibrin. Consequently, complexes of u-PA and PAI-1 dissociate from the fibrin matrix and are encountered in the fluid phase. In contrast, t-PA/PAI-1 complexes remain bound to fibrin. By employing recombinant t-PA deletion-mutant proteins, that precisely lack domains involved in fibrin binding, we demonstrate that binding of t-PA/PAI-1 complexes is mediated by both the "finger" (F) and the "kringle-2" (K2) domain of t-PA. A model is proposed that explains inhibition of the fibrinolytic process, at the level of plasminogen activation by t-PA, directed by PAI-1 bound to fibrin. An implication of the proposed model is that t-PA/PAI-1 complexes and free t-PA compete for the same binding sites on fibrin.
PMCID: PMC548928  PMID: 2503541
14.  Molecular cloning of a gene abundantly expressed during fruiting body initiation in Schizophyllum commune. 
Journal of Bacteriology  1984;157(3):802-808.
Complementary DNA was synthesized on polyadenylated RNA from a dikaryotic mycelium of the basidiomycete Schizophyllum commune bearing fruiting body initials. The complementary DNA was cloned into the PstI site of pBR327 by the deoxyguanidylate-deoxycytidylate tailing approach. After transformation into Escherichia coli cells, a differential screening was performed by colony hybridization with complementary [32P]DNA made on the RNAs of the monokaryon and dikaryon strains. Two clones were selected for further analysis by Northern blotting and hybrid release translation. Clone 1D10 hybridized with an mRNA of 775 nucleotides, coding for a polypeptide with an Mr of 15,000. Although this RNA was present in both monokaryotic and dikaryotic mycelia, its concentration appeared to change considerably over time and with different cultivation conditions. This mRNA is probably the most abundantly expressed sequence in S. commune. Clone 1G2 and its homologs hybridized with an mRNA of 650 nucleotides, coding for a polypeptide with an Mr of 13,000. This gene was exclusively expressed in the dikaryon strain. In liquid-grown cultures, the concentration of this mRNA was low but increased ca. 20-fold during the establishment of fruiting body primordia. A chromosomal fragment of 9 kilobase pairs which contained the 1G2 gene was cloned into pBR327 and used as a probe in Northern blot hybridization. It was found that surrounding sequences were not expressed at the same time or to the same extent as the 1G2 gene.
PMCID: PMC215330  PMID: 6142033
15.  Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. 
Nucleic Acids Research  1985;13(13):4699-4717.
Von Willebrand Factor (vWF) mRNA was identified in fractionated polyA+ RNA preparations isolated from cultured human endothelial cells. Micro-injection of specific polyA+ RNA fractions in Xenopus laevis oocytes provoked the synthesis of a vWF-like product which could be detected with an immunoradiometric assay relying on Sepharose-linked monoclonal anti-vWF IgG and different radiolabeled monoclonal anti-vWF IgGs. A vWF-mRNA-containing polyA+ RNA preparation served as substrate for a size-selected cDNA-expression library of 60 000 colonies which was screened for the synthesis of antigens related to vWF, using polyclonal anti-vWF IgG and a second antibody conjugated with peroxidase. Eight positive colonies were detected of which two reacted strongly in the enzyme-linked assay. Immunoblotting of bacterial extracts of "expression clones" with a monoclonal anti-vWF IgG revealed polypeptides which size fits within the length of the cDNA insertions. Northern blotting of human endothelial RNA, employing fragments of vWF cDNA as probes, showed specific hybridization with a mRNA of about 9000 nucleotides. DNA-sequence analysis of a vWF-cDNA insertion revealed an open reading frame followed by a translation stopcodon. It is argued that the cDNA insertions encode the carboxy-terminal part of the vWF protein. vWF-cDNA probes were employed to map the von Willebrand factor gene on chromosome 12 using a panel of 35 human-rodent somatic cell hybrids.
PMCID: PMC321821  PMID: 3875078

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