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ABSTRACT: Despite evidence of the overuse of acid suppressive medication for gastroesophageal reflux disease (GERD), a transfer to noncontinuous therapy after long-term treatment proves difficult. Aim: To quantify the effect of blinded dosage reduction after long-term therapy on symptom control and quality of life while assessing pharmacological and placebo needs.
Primary care patients with a history of GERD and long-term treatment were randomized to daily placebo with pantoprazole rescue (n = 141) or daily pantoprazole with placebo rescue (n = 62) upon relief after 4 weeks pantoprazole 20 mg. The number of rescue tablets, symptom control and generic quality of life were analyzed.
Measured from the daily placebo arm, 19% of the patients terminated treatment, 33% managed with 2-6 tablets/week, 38% needed a daily dosage and 10% needed more than a daily dosage in the long run. At these final dosages, symptom control and quality of life were dosage-independent and, furthermore, equal to values of patients on fixed daily pantoprazole. A temporal decrease in well-being was seen in 24% of the patients.
A significant placebo response is apparent in long-term users of acid suppressive medication and pharmacological dependency is overestimated. Despite their history of long-term treatment, the majority of GERD patients can be switched from daily to on-demand treatment without impairing symptom control and quality of life.
Digestion 12/2009; 81(1):43-52. · 2.05 Impact Factor
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ABSTRACT: The aim of this study was to explore determinants of residual reflux symptoms among patients with gastroesophageal reflux disease (GERD) despite maintenance treatment with acid suppressive medication (ASM).
Primary care GERD patients on chronic ASM were classified as symptom-free (55%) or symptomatic (45%) according to the impact of their residual reflux symptoms (QolRad). They were compared with respect to lifestyle (BMI, alcohol, smoking, physical exercise), compliance (daily ASM dosage), disease history, psychological factors (SCL-90) and quality of life (SF-36).
None of the investigated lifestyle factors, nor dosage and disease history were related to residual symptoms. However, symptomatic patients differed from patients with relief on all psychological and quality of life dimensions. In a multiple logistic regression model somatization, hostility, mental health, body pain, as well as gender were independently associated with residual symptoms; the derived ROC curve had an AUC of 0.78.
The majority of GERD patients is symptom-free on chronic ASM; they display a healthy psychological state and high quality of life. Residual symptoms however, are associated with psychological distress and lower quality of life. Recognition of this subgroup might hold the key to improving long-term management of gastroesophageal reflux.
Digestion 08/2008; 77(3-4):207-13. · 2.05 Impact Factor
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ABSTRACT: Many DNA constructs are generated for protein expression studies. Translational properties and mRNA stability are crucial aspects that have to be accounted for during DNA construction. An optimized vector for protein overexpression studies is described considering elements in the mature mRNA that influence translatability and stability. Recommendations regarding vector construction for Xenopus laevis embryo injection are provided, based on literature and experimental data. The 5'untranslated region (5'UTR) should be non-regulated, short, unstructured, and without AUG codons. The sequence around the start codon should match the initiation context of the species studied (ACCAUGG, for vertebrates), and the open reading frame should be cloned with its own stop codon, followed by a G or A residue. Furthermore, the 3'UTR should be non-regulated, and a strong polyadenylation signal must be included in DNA vectors. In RNA template vectors, the presence of a poly(A) or AC tail is essential for stability, as well as for translation efficiency in mRNA injection experiments. These aspects result in high-level expression of exactly the desired protein. Easily obtainable examples of the sequences [5'UTR, 3'UTR, and poly(A) signal] are suggested.
BioTechniques 10/2001; 31(3):572, 574, 576-80, passim. · 2.67 Impact Factor
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ABSTRACT: The properties of the architecturally complex Xenopus laevis TGFbeta5, PDGF-A and PDGF-alpha receptor 5'UTRs were investigated. 5' extended cDNAs were obtained by 5'RACE, resulting in long 5'UTRs (478-710 nt) with multiple upstream AUGs (3-13), andthe potential to fold into stable structures. Injection studies suggested that the cloned PDGF-alphaR 5'UTR contains an intron. Splicing at potential 5' and 3' splice sites would result in a non-complex 5'UTR of 142 nt. The above mentioned 5'UTR characteristics are inhibitory for ribosomal scanning. Indeed, relative to the beta-globin 5'UTR, the complex 5'UTRs strongly repressed initiation of protein synthesis in pre-MBT Xenopus embryos. However, later in embryogenesis, the inhibition was partly relieved. The results show temporal translational control by these 5'UTRs. Transgenic embryos showed that the 5'UTRs allowed translation throughout the embryo; spatial control could not be observed. Interestingly, a fragment in the PDGF-A 5'UTR highly similar to an element in the human PDGF-A 5'UTR is complementary to Xenopus 18S ribosomal RNA. None of these Xenopus 5'UTRs contains an IRES, as determined by injecting bicistronic constructs.
The International Journal of Developmental Biology 01/2001; 44(8):851-9. · 2.82 Impact Factor
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ABSTRACT: A number of growth factors, whose spatio-temporal expression is essential for embryonic development, are encoded by mRNAs with a complex 5'UTR. Human insulin-like growth factor 2 mRNA contains a long (592 nucleotides) 5'UTR (IGFl1) with one upstream open reading frame and stable stem-loop structures, elements which might be important for controlled translation. To investigate whether these unusual features of IGFl1 can control translation initiation during embryogenesis, we examined the initiation efficiency on this 5'UTR during development of Xenopus laevis. The results demonstrate that IGFl1 strongly represses translation of a reporter in early embryos, compared with the Xenopus beta-globin 5'UTR. The inhibition is alleviated soon after the midblastula transition, suggesting a stimulatory effect of the transcription start. However, a similar stimulation of IGFl1-driven translation is seen in embryos in which de novo transcription was inhibited by actinomycin D. Furthermore, it is shown that up-regulation of IGFl1 activity is independent of eIF4E levels, and activity of IGFl1 is observed in all tissues of transgenic Xenopus embryos. These results indicate that post-translational modulation of a trans-acting factor enables efficient initiation on this complex 5'UTR after the midblastula transition.
The International Journal of Developmental Biology 01/2001; 44(8):843-50. · 2.82 Impact Factor
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ABSTRACT: Cap-dependent ribosomal scanning occurs on the majority of cellular 5' UTRs. This process is severely hampered on long 5' UTRs, containing AUGs and secondary structure. These characteristics are often found in mRNAs encoding regulatory proteins like proto-oncogenes, growth factors, their receptors, and homeodomain proteins. A number of these mRNAs use an alternative mechanism of translation initiation, involving an internal ribosomal entry site (IRES). Cellular mRNAs containing a complex 5' UTR or an IRES share an intriguing characteristic: their translational efficiency can be very specifically regulated by their 5' UTR, providing post-transcriptional regulation. During embryonic development, the 5' UTRs of Antp. Ubx RAR beta 2 c-mos and c-myc regulate protein expression in a spatio-temporal manner. Translation initiation on a number of growth factor RNAs (IGFII, PDGF2, TGF beta, FGF-2, and VEGF) is specifically regulated during differentiation, growth, and stress. Furthermore, 5' UTR activity, mutations in the 5' UTR, or the occurrence of alternative 5' UTRs have been implicated in the progression of various forms of cancer. The mechanisms involved in 5' UTR mediated control are not well understood. Binding of trans-acting factors could mediate translation stimulation or repression. Furthermore, the precise localization of upstream AUGs and the activity of the cap-binding initiation factor 4E are suggested to be important for translation regulation of these mRNAs. This review focuses on 5' UTRs whose activity is regulated, the processes during which this regulation occurs, and as far as known the mechanisms involved.
The International Journal of Biochemistry & Cell Biology 02/1999; 31(1):87-106. · 4.63 Impact Factor
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ABSTRACT: To establish whether or not local low-dose recombinant interleukin-2 (rIL-2) therapy might result in therapeutic benefit for ovarian cancer patients treated with cisplatin, the antitumour effects of rIL-2 and of combined treatment with cisplatin and rIL-2 in a mouse ovarian tumour (MOT) model were studied. In addition, some possible mechanistic aspects underlying the observed antitumour responses were analysed. MOT cells were injected i.p. into syngeneic, immunocompetent, female C3HeB mice. Tumour-bearing mice received i.p. treatment with cisplatin, rIL-2 or both. The MOT tumour appeared to be hardly responsive to treatment with cisplatin only or rIL-2 only. In contrast, combined local treatment with low doses of cisplatin (1 and 5 mg/kg body weight) and rIL-2 (60000 U/day) resulted in an effective antitumour response in MOT-bearing mice. Complete rejection of the i.p. (local) tumour occurred in up to 60% of the cases. In vitro studies showed that cisplatin and rIL-2 do not have cumulative direct toxic effects on MOT cells. Mice cured after combined treatment with cisplatin and rIL-2 were not able to reject a rechallenge with tumour cells, indicating that these mice had not developed immunity to the tumour. Analysis of tumour-associated leucocytes, however, showed that combined treatment with cisplatin and rIL-2 did result in enhanced non-specific cytolytic activity of peritoneal leucocytes. We have thus demonstrated that, in the MOT model, combined local treatment with low doses of cisplatin and of rIL-2 is far more effective than therapy with cisplatin alone. Non-specific cytotoxicity of leucocytes appears to be involved in antitumour responses induced by combined treatment with cisplatin and rIL-2. These results suggest that, in human ovarian carcinoma, much better results may be obtained with the combined treatment of cisplatin and low (non-toxic) doses of rIL-2 than with cisplatin only. This may also apply to cisplatin-resistant ovarian carcinoma.
Cancer Immunology and Immunotherapy 03/1998; 46(1):41-7. · 3.70 Impact Factor
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ABSTRACT: The efficacy with which disseminated SL2 and P815 tumors, in syngeneic DBA/2 mice, can be eradicated with low-dose recombinant interleukin-2 (rIL-2) therapy is about equal. Treatment (i.p.) of DBA/2 mice, injected i.p. with SL2 or P815 cells on day 0, with rIL-2 (Proleukin) on days 10 to 14 results in a cure rate of 50 to 60% in each case. The in vitro sensitivity of SL2 and P815 cells to cis-diammine-dichloro-platinum [II] (cisplatin) is also comparable, although P815 appears to be slightly more sensitive. In vivo, however, therapy with cisplatin is far less effective against P815 than against SL2. In the DBA/2-SL2 model, at all doses tested, combination therapy with cisplatin (administered on day 2) and rIL-2 (administered on days 10-14) resulted in anti-tumor efficacy greater than that of either drug separately. In contrast, in the DBA/2-P815 model, cisplatin decreased the anti-tumor efficacy of subsequently applied rIL-2 therapy. As the only difference between the 2 tumor models is the tumor itself, the success of combination therapy with cisplatin and rIL-2 was dependent on tumor characteristics. We suggest that in these 2 tumor models, neither the sensitivity of these tumors to cisplatin nor their growth and dissemination patterns were responsible for the contrasting results of combination therapy in these models. Instead, tumor-dependent immune-modulating effects of cisplatin may be the cause of these effects. These immune-modulating effects may comprise (a) effects of cisplatin on the tumor cells, resulting in changes in their susceptibility to immune effector cells, or changes in their immunogenicity; (b) activating or suppressive effects of cisplatin on immune effector cells; or (c) a combination of these effects. These effects could then either synergize or antagonize with the immune activating properties of rIL-2.
International Journal of Cancer 06/1993; 54(3):513-7. · 5.44 Impact Factor
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A.W. van der Velden
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ABSTRACT: The aetiology of gastro-oesophageal reflux disease (GORD) is known to be heterogeneous. Several studies have indicated a relationship between GORD and psychological distress, e.g. anxiety, depression, somatization, phobia and obsessionality. Initially, these relations were explained by ‘‘health-care seeking behaviour’’, but after confirmation in community- based studies a causal interaction between psychological distress and reflux disease was considered likely. However, cross-sectional studies with symptomatic patients cannot elucidate cause and effect, leaving the question ‘‘does psychological distress cause oesophageal symptomatology or vice versa’’ unanswered. Our aim was to add evidence to these interactions by studying the psychological state and quality of life of GORD patients treated with acid suppressive medication (ASM) to relieve their symptoms
