[show abstract][hide abstract] ABSTRACT: There is accumulating evidence of a genetic predisposition for developing a functional gastrointestinal (GI) disorder. Identification of the genetic factors may improve understanding of underlying pathophysiological mechanisms. We aimed to test the association of functional polymorphisms in genes involved in serotonergic signalling and G-protein-mediated signal transduction, both affecting gastroduodenal sensory and motor function, with functional dyspepsia (FD). FD patients, send to our tertiary referral centre, were studied (n = 112). Healthy controls (n = 336) free of GI symptoms were matched 1 : 3 for age and gender. Polymorphisms in genes encoding the serotonin receptor type three A subunit (HTR3A), the serotonin transporter (SERT) and the G-protein beta3 subunit (GNB3) were analysed. The FD patients displayed a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls (OR = 1.60, 95% CI: 1.03-2.49, P = 0.038). No association between FD and the genotype of the insertion/deletion polymorphism in the promoter of SERT (SERT-P) or HTR3A C178T polymorphism was observed. Tertiary referral FD is associated with the 825T allele of the GNB3 gene. The increased signal transduction associated with this allele may contribute to the abnormalities in gastroduodenal sensory and motor function observed in FD.
Neurogastroenterology and Motility 08/2008; 20(7):767-73. · 2.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study assessed psychological distress during the first year after diagnosis in breast cancer patients approached for genetic counseling at the start of adjuvant radiotherapy and identified those vulnerable to long-term high distress. Of the approached patients some chose to receive a DNA test result (n = 58), some were approached but did not fulfill criteria for referral (n = 118) and some declined counseling and/or testing (n = 44). The comparative group consisted of patients not eligible for genetic counseling (n = 182) and was therefore not approached. Patients actively approached for genetic counseling showed no more long-term distress than patients not eligible for such counseling. There were no differences between the subgroups of approached patients. Predictors for long-term high distress or an increase in distress over time were pre-existing high distress and a low quality of life, having children, and having no family members with breast cancer. It is concluded that breast cancer patients can be systematically screened and approached for genetic counseling during adjuvant radiotherapy without imposing extra psychological burden. Patients vulnerable to long-term high distress already displayed high distress shortly after diagnosis with no influence of their medical treatment on their level of distress at long-term.
Breast Cancer Research and Treatment 07/2008; 109(3):507-14. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Serotonin (5-HT) is involved in the regulation of motoric and sensory functions of the upper gastrointestinal tract. The aim of the current study was to determine whether serotonergic signalling is altered in patients with idiopathic gastroparesis. Mucosal biopsy specimens were collected from the duodenum, antrum and fundus of 11 patients with idiopathic gastroparesis and 11 healthy controls. Neuroendocrine cells, specifically 5-HT producing cells, were counted after immunohistochemistry, and non-neuronal mRNA expression levels of tryptophan hydroxylase (TPH)-1, 5-HT transport protein (SERT), 5-HT3 and 5-HT4 receptor were quantified by real time RT-PCR. The number of 5-HT producing cells was comparable between patients and controls. No difference in expression of TPH-1 (rate limiting enzyme in 5-HT biosynthetic pathway) and SERT (responsible for 5-HT uptake) was found between patients and controls (P > 0.05). In the duodenum, the expression of the 5-HT3 receptor subunits and the 5-HT4 receptor was comparable between both groups. However, the 5-HT4(c) splice variant was expressed more abundantly in healthy controls compared to patients (P = 0.015). This study suggests that the delayed gastric emptying and upper abdominal symptoms in idiopathic gastroparesis do not result from altered mucosal 5-HT biosynthetic and uptake capacity.
Neurogastroenterology and Motility 06/2008; 20(5):448-55. · 2.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the relationship between gastric function and upper abdominal sensations we studied sixty FD patients (43 female). All patients underwent three gastric function tests: (13)C octanoic gastric emptying test, three-dimensional ultrasonography (proximal and distal gastric volume), and the nutrient drink test. Upper abdominal sensations experienced in daily life were scored using questionnaires. Impaired proximal gastric relaxation (23%) and a delayed gastric emptying (33%) are highly prevalent in FD patients; however, only a small overlap exists between the two pathophysiologic disorders (5%). No relationship was found between chronic upper abdominal symptoms and gastric function (proximal gastric relaxation, gastric emptying rate, or drinking capacity) (all P > 0.01). Proximal gastric relaxation or gastric emptying rate had no effect on maximum drinking capacity (P > 0.01). The lack of relationship between chronic upper abdominal sensations and gastric function questions the role of these pathophysiologic mechanisms in the generation of symptoms.
Digestive Diseases and Sciences 05/2008; 53(5):1223-30. · 2.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the methodological quality of randomized controlled trials (RCTs) of systemic antibiotic prophylaxis in severe acute pancreatitis in relation to outcome.
The MEDLINE, EMBASE and Cochrane databases were searched for RCTs that studied the effectiveness of systemic antibiotic prophylaxis in severe acute pancreatitis. A meta-analysis was performed with a random effects model. Methodological quality was quantified by a previously published scoring system (range 0-17 points).
Six studies, with a total of 397 participants, obtained a methodological score of at least 5 points and were included. Systemic antibiotic prophylaxis had no significant effect on infection of pancreatic necrosis (absolute risk reduction (ARR) 0.055; 95% CI -0.084 to 0.194) and mortality (ARR 0.058, 95% CI -0.017 to 0.134). Spearman correlation showed an inverse association between methodological quality and ARR for mortality (correlation coefficient -0.841, p = 0.036).
The inverse relationship between methodological quality and impact of antibiotic prophylaxis on mortality emphasizes the importance of high-quality RCTs. At present, adequate evidence for the routine use of antibiotic prophylaxis in severe acute pancreatitis is lacking.
[show abstract][hide abstract] ABSTRACT: Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (-44G --> A and +71A --> G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals.
Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic).
We found a significant contribution of the minor Cx40 allele or genotype (-44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the -44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (-44GG; P = 0.033).
These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.
Journal of Hypertension 03/2006; 24(2):325-30. · 3.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the most adequate parameter to measure the consequences of reducing the parotid gland dose.
One hundred eight patients treated with radiotherapy for various malignancies of the head and neck were prospectively evaluated using three methods. Parotid gland function was objectively determined by measuring stimulated parotid flow using Lashley cups and scintigraphy. To assess xerostomia-related quality of life, the head-and-neck cancer module European Organization for Research and Treatment of Cancer QLQ (Quality of Life Questionnaire) H&N35 was used. Measurements took place before radiotherapy and 6 weeks and 12 months after the completion of radiotherapy. Complication was defined for each method using cutoff values. The correlation between these complications and the mean parotid gland dose was investigated to find the best measure for parotid gland function.
For both flow and scintigraphy data, the best definition for objective parotid gland toxicity seemed to be reduction of stimulated parotid flow to < or =25% of the preradiotherapy flow. Of all the subjective variables, only the single item dry mouth 6 weeks after radiotherapy was found to be significant. The best correlation with the mean parotid gland dose was found for the stimulated flow measurements. The predictive ability was the highest for the time point 1 year after radiotherapy. Subjective findings did not correlate with the mean parotid dose.
Stimulated flow measurements using Lashley cups, with a complication defined as flow < or =25% of the preradiotherapy output, correlated best with the mean parotid gland dose. When reduction of the mean dose to the parotid gland is intended, the stimulated flow measurement is the best method for evaluating parotid gland function.
International Journal of Radiation OncologyBiologyPhysics 12/2005; 63(4):1006-9. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Irradiation of the parotid glands causes salivary dysfunction, resulting in reduced salivary flow. Recovery can be seen with time; however, long-term prospective data are lacking. The objective of this study was to analyze the long-term parotid gland function after irradiation for head-and-neck cancer.
A total of 52 patients with head-and-neck cancer and treated with radiotherapy (RT) were prospectively evaluated. Stimulated bilateral parotid salivary flow rates were measured before RT and 6 weeks, 6 months, 12 months, and at least 3.5 years after RT completion. A complication was defined as a stimulated parotid flow rate of <25% of the pre-RT flow rate. The normal tissue complication probability model proposed by Lyman was fit to the data. Multilevel techniques were used to model the patterns of flow rates with time.
The mean stimulated flow rate of the parotid glands before RT was 0.31 mL/min (standard deviation [SD], 0.21). This was reduced to 0.14 mL/min (SD, 0.15) at 6 weeks after RT and recovered to 0.20 mL/min (SD, 0.22) at 6 months and 0.19 mL/min (SD, 0.21) at 12 months after RT. The mean stimulated flow rate was 0.25 mL/min (SD, 0.28) 5 years after RT. The mean dose to the parotid gland resulting in a 50% complication probability increased from 34 Gy at 6 weeks to 40 Gy at 6 months, 42 Gy at 12 months, and 46 Gy at 5 years after RT. Multilevel modeling indicated that both dose and time were significantly associated with the flow ratio.
Salivary output can still recover many years after RT. At 5 years after RT, we found an increase in the salivary flow rate of approximately 32% compared with at 12 months after RT.
International Journal of Radiation OncologyBiologyPhysics 08/2005; 62(3):659-64. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated how different parameters affect oral size perception of small particles of SiO2 and polystyrene particles of varying sizes (2–230 μm). Eighteen healthy subjects assessed the size of the particles by rubbing the sample between the tongue and the palate. The importance of size and type were studied by direct scaling and forced choice ranking and the results of the two methods were compared. To assess the relative importance of the tongue and the palate in oral size perception topical anesthesia was applied. The size and characteristics of particles are of importance for perception of particle size, where hard and irregular particles are perceived as larger than soft and round particles of similar size. The two methods of size perception, direct scaling and forced ranking produce very similar results on oral size perception. Topical anesthesia of either the tongue or the palate had no significant effect.
[show abstract][hide abstract] ABSTRACT: Aim: To evaluate the methodological quality of randomized controlled trials (RCTs) of systemic antibiotic prophylaxis in severe acute pancreatitis in relation to outcome. Methods: The MEDLINE, EMBASE and Cochrane databases were searched for RCTs that studied the effectiveness of systemic antibiotic prophylaxis in severe acute pancreatitis. A meta-analysis was performed with a random effects model. Methodological quality was quantified by a previously published scoring system (range 0-17 points). Results: Six studies, with a total of 397 participants, obtained a methodological score of at least 5 points and were included. Systemic antibiotic prophylaxis had no significant effect on infection of pancreatic necrosis (absolute risk reduction (ARR) 0.055; 95% CI -0.084 to 0.194) and mortality (ARR 0.058, 95% CI -0.017 to 0.134). Spearman correlation showed an inverse association between methodological quality and ARR for mortality (correlation coefficient -0.841, p = 0.036). Conclusions: The inverse relationship between methodological quality and impact of antibiotic prophylaxis on mortality emphasizes the importance of high-quality RCTs. At present, adequate evidence for the routine use of antibiotic prophylaxis in severe acute pancreatitis is lacking. Copyright (c) 2007 S. Karger AG, Basel and IAP.