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Biomedical subjects

J F Rehfeld

Publications and source records attributed to J F Rehfeld.

At least 19 recordsLinked to original sources
PubMed2006

Ghrelin stimulates gastric emptying and hunger in normal-weight humans.

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

Adult↗
PubMed2006

BNP and N-terminal proBNP are both extracted in the normal kidney.

BACKGROUND: Increased plasma concentrations of cardiac-derived B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (proBNP) are both associated with left ventricular dysfunction. Information on the regional elimination of the peptides is, however, still scarce. We therefore examined the renal and peripheral extraction of N-terminal proBNP and BNP. MATERIALS AND METHODS: The study comprised 18 patients with essential arterial hypertension, 51 with cirrhosis, and 18 control patients without kidney or liver disease. All patients underwent a haemodynamic investigation with catheterization of the femoral artery and femoral and renal veins. Blood sampling from the catheters allowed determination of the arteriovenous extraction ratio of N-terminal proBNP and BNP. RESULTS: Neither the peripheral N-terminal proBNP (13, 11, 19 pmol L(-1), NS) nor the BNP plasma concentrations (4, 12, 9 pmol L(-1), NS) differed between the patient groups. In addition, similar renal extractions were observed in the groups. The renal extraction of N-terminal proBNP (0.16) was not different from that of BNP (0.16). In contrast, the N-terminal proBNP extraction in the lower extremity was markedly lower compared with BNP (0.00 vs. 0.125, P = 0.007). CONCLUSIONS: A comparable renal elimination of N-terminal proBNP and BNP is contrasted by a selective extraction of BNP in the lower extremity. Our results suggest a different elimination mechanism in the renal and peripheral circulation, which partly may explain the higher N-terminal proBNP compared with BNP concentrations in normal plasma.

Aged↗
PubMed2006

No association between the -399 C > T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population.

OBJECTIVE: A polymorphism in the promoter region of the NPY gene at position -399 C > T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population. METHOD: We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716). RESULTS: We detected the polymorphism -399 C > T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups. CONCLUSION: The lack of association between the -399 C > T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Adult↗
PubMed2005

Increased circulating endothelins are not of cardiopulmonary origin in heart failure patients.

OBJECTIVE: Plasma concentrations of endothelin-1 and big-endothelin are increased in heart failure patients. However, the precise contribution of endothelin secretion from the cardiopulmonary system remains unresolved. The aim of this study was to investigate whether the cardiopulmonary system contributes to the circulating endothelin-1 and big-endothelin concentrations in heart failure patients. MATERIAL AND METHODS: Blood samples were obtained at right heart catheterization from different cardiovascular regions including the coronary sinus in chronic heart failure patients (n=12) and from age-matched control subjects (n=12). RESULTS: The peripheral plasma concentrations of endothelin-1 were almost 3-fold higher in heart failure patients compared with the control subjects (1.25 pmol/l, 0.30-8.20 pmol/l (median, range) versus 0.46 pmol/l, 0.10-0.88 pmol/l, p<0.01). However, the endothelin-1 concentration was approximately 25% lower in plasma samples from the coronary sinus than in plasma from the inferior caval vein (p<0.05) in the heart failure patients. There were no differences in big-endothelin concentrations between any of the cardiovascular regions. CONCLUSIONS: In heart failure patients, increased plasma concentrations of endothelin-1 and big-endothelin mainly reflect an increased secretion from the peripheral endothelium.

Adult↗
PubMed2004

Acute myocardial hypoxia increases BNP gene expression.

It is well established that cardiac failure increases cardiac B-type natriuretic peptide (BNP) expression due to myocardial stretching. However, patients with ischemic heart disease also display increased plasma BNP and proBNP concentrations despite preserved cardiac function. In this study, we examined whether acute myocardial hypoxia increases cardiac BNP expression. Surgical reduction of the blood flow to an area of the anterior ventricular wall in pigs reduced the myocardial oxygen tension from 46 +/- 4 to 13 +/- 5 mmHg. The tissue contents of VEGF and BNP mRNA increased 1.8-fold and 3.5-fold, respectively (n=10, P<0.005) in hypoxic compared with normoxic ventricular myocardium after 2.2 +/- 0.2 h; the magnitude of the increase in BNP mRNA expression was positively correlated with that of VEGF in hypoxic myocardium (r=0.66, P<0.05). In support of a hypoxia-induced increase of BNP gene transcription, the content of a premature BNP mRNA was increased in hypoxic myocardium (4.8-fold, P<0.005) and in freshly harvested ventricular myocytes when kept in culture flasks and oxygen-deprived for 3 h (2.2-fold, P=0.002). ProBNP peptide accumulated in the medium of freshly harvested ventricular myocyte cultures but was undetectable in ventricular myocardium, indicating rapid release of the newly synthesized proBNP peptide. Accordingly, the plasma proBNP concentration increased after 2 h of myocardial hypoxia (P=0.028). Cumulatively, the data suggest that acute hypoxia stimulates cardiac BNP expression.

Animals↗
PubMed2004

Different effects of whole milk and a fermented milk with the same fat and lactose content on gastric emptying and postprandial lipaemia, but not on glycaemic response and appetite.

Longitudinal studies indicate that milk and fermented milk products lower basal plasma cholesterol concentrations, despite their high content of saturated fat, and therefore have favourable health effects. However, there have been few studies on the postprandial effects of milk products. The present study compared the effect of whole milk with a fermented milk, A-38, on postprandial carbohydrate and lipid metabolism, gastric emptying and appetite. Eight healthy young men participated. On the two test days, they arrived fasting for collection of baseline values before consuming the meals, which for a 75 kg subject consisted of 1.4 litre milk or fermented milk, plus 165 mg [13C]acetate (for later determination of gastric emptying by a [13C]acetate breath test). Lactose (15 g) was added to the A-38 meal to equalize the lactose content. Postprandially the A-38 meal resulted in a slower gastric emptying rate than milk (P<0.001). Furthermore, the A-38 meal resulted in a greater increase and a quicker decrease of the triacylglycerol content in all lipoprotein fractions (LDL-fraction, P<0.05; other fractions, P<0.001) and of the gastrointestinal hormones (cholecystokinin and peptide YY, P<0.05; gastric inhibitory polypeptide and glucagon-like polypeptide-1, P<0.001). There were no significant differences in appetite sensations (measured by visual analogue scale) or in the glucose and insulin response (P>0.10). The slower emptying rate of the liquid phase after the A-38 meal is probably due to the higher viscosity of A-38. The lower and more prolonged triacylglycerol response after the milk meal might be caused by coagulation of milk in the stomach.

Adult↗
PubMed2004

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation.

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Adenosine Triphosphatases↗
PubMed2003

Increased cardiac BNP expression associated with myocardial ischemia.

Congestive heart failure is accompanied by increased cardiac brain natriuretic peptide (BNP) gene expression with elevated plasma concentrations of BNP and its precursor, proBNP. We investigated if myocardial ischemia in the absence of overt heart failure may be another mechanism for increased myocardial BNP expression. The BNP expression was examined in hypoxic myocardium of patients undergoing coronary bypass grafting surgery, in patients with coronary artery disease and normal left ventricular function undergoing percutaneous transluminal intervention therapy, and in heart failure patients without coronary artery disease. BNP mRNA was quantified by real-time PCR, and plasma BNP and proBNP concentrations were measured with radioimmunoassays. Quantitative analysis of BNP mRNA in atrial and ventricular biopsies from coronary bypass grafting patients revealed close associations of plasma BNP and proBNP concentrations to ventricular, but not atrial, BNP mRNA levels. Plasma BNP and proBNP concentrations were markedly increased in patients with coronary artery disease but without concomitant left ventricular dysfunction. These results are compatible with the notion that myocardial ischemia, even in the absence of left ventricular dysfunction, augments cardiac BNP gene expression and increases plasma BNP and proBNP concentrations. Thus, elevated BNP and proBNP concentrations do not necessarily reflect heart failure but may also result from cardiac ischemia.

Angioplasty, Balloon, Coronary↗
PubMed2003

Progastrin and its products from patients with chronic viral hepatitis and liver cirrhosis.

BACKGROUND: Gastrin and its precursor, progastrin, are synthesized in the stomach, particularly when infected with Helicobacter pylori, and they are metabolized, at least in part, in the liver. However, little is known about their levels in various hepatic diseases. METHODS: This study was carried out on 147 patients including chronic hepatitis B (n = 35), hepatitis C (n = 52) and liver cirrhosis (n = 60) of class A (n = 38), class B (n = 15) and class C (n = 7) (Child-Pugh classification) and age- and sex-matched healthy controls (n = 65). The diagnosis of chronic hepatitis was confirmed by liver biopsy in all patients, whereas the diagnosis of liver cirrhosis was based on clinical and laboratory findings. Liver biopsy was done in 38 out of 60 patients. Blood samples were collected under basal conditions and separated plasma samples were kept frozen at -70 degrees C until radioimmunoassay of progastrin and its products, including bioactive amidated gastrins. RESULTS: Median (range) plasma concentrations of total progastrin product and amidated gastrin in control subjects were 147.5 (73-345) pM and 33 (15-65), respectively. These concentrations in hepatitis B and C were not significantly different from those in controls. In cirrhosis (classes A, B and C), the concentrations of the progastrin and of gastrin were significantly (P < 0.05) higher than in controls reaching, respectively, 253.5 (135-683 pM) and 47.5 (17-385) pM. Both progastrin and gastrin levels were significantly higher in H. pylori-positive than in negative cirrhotic patients. Antibodies against H. pylori were present in about 50% of controls, 68% of hepatitis B, 57% of hepatitis C and in 83% in cirrhosis patients. The difference in H. pylori prevalence between cirrhosis and controls was statistically significant. CONCLUSIONS: Plasma levels of progastrin and gastrin are significantly increased in cirrhotic patients and this could be attributed to reduced metabolism of these peptides in liver cirrhosis and to their increased release due to H. pylori infection rate in this disease.

Adolescent↗
PubMed2003

The posttranslational phase of gene expression: new possibilities in molecular diagnosis.

Proteins in general and secretory proteins in particular undergo posttranslational processes before they reach the structure in which they can fulfill their functional purpose. The protein precursor may undergo a wide variety of proteolytic cleavages, N- and C-terminal trimmings and amino acid derivatizations in cells that express the protein. Occasionally, the same precursor is differently processed in different cell types and, in addition, diseased cells may process a given precursor abnormally. For instance, the translational process is often either increased or decreased in diseased cells, which render the ensuing modifications of the precursor incomplete. As a result, a variable mixture of precursors and processing-intermediates accumulates. Measurement of a single protein or peptide component of the posttranslational processing cascade may not facilitate the diagnosis of a disease, because the pattern of precursors and processing products vary individually among patients. In order to exploit disturbed posttranslational processing for diagnostic use, and--at the same time--provide an accurate measure of the translational product, a simple analytical principle named "processing-independent analysis" (PIA) has been designed. PIA-methods quantitate the total mRNA product irrespective of the degree of precursor processing. PIA-methods have recently been developed for a number of prohormones and neuroendocrine proteins, and their diagnostic potential appears promising in early diagnosis of tumors and cardiovascular diseases. The present review describes posttranslational processing patterns for some neuroendocrine proteins. Second, PIA-measurements of precursor-products are mentioned with indication of problems and pitfalls. Finally, PIA-results obtained in diagnosis of neoplastic and cardiovascular diseases are highlighted. But first general aspects of the posttranslational processing are reviewed as a necessary basis for the understanding of the new diagnostic possibilities.

Animals↗
PubMed2003

On the tissue-specific processing of procholecystokinin in the brain and gut--a short review.

Cholecystokinin (CCK) is a major peptide hormone in the gut and a major peptide transmitter in the brain. Its synthesis requires endoproteolytic cleavage of proCCK at several mono- and dibasic sites by prohormone convertases (PCs). Of these, PC1 and PC2 are expressed in cerebral neurons and intestinal endocrine cells. Characteristically, however, the processing of proCCK varies markedly between the brain and the gut. In neurons, CCK-8 is always the predominating form, whereas the endocrine gut cells (I-cells) contain a mixture of small and larger CCK-peptides of which CCK-33 or CCK-22 often predominate. The role of PC1 and PC2 in the processing of proCCK have now been examined by measuring the concentrations of prohormone, processing intermediates and amidated end-products in jejunal and cerebral extracts of PC1 and PC2 deficient mice and corresponding wild type controls. The PC1 null mice revealed a pattern opposite to that of the PC2 null mice, in whom only the cerebral processing of proCCK was affected. Thus PC1 knockouts reveal a severe block in the processing of intestinal proCCK. Accordingly, the intestinal concentration of proCCK was many fold increased, and also the concentrations of different processing intermediates were raised; but the concentration of bioactive, alpha-amidated and O-sulfated CCK was reduced to a few percent of normal. The only bioactive CCK peptide in the gut of PC1 deficient mice was CCK-22, and it was present only in trace amounts. The cerebral processing of proCCK was, however, not at all affected by the lack of PC1 - in sharp contrast to the effect of PC2. The results show that the tissue-specific processing of proCCK to a large extent can be explained by prohormone convertases, as PC1 plays a decisive role in the maturation of hormonal CCK in the gut, whereas PC2 governs the processing of brain proCCK.

Animals↗
PubMed2002

Intraduodenal conjugated bile salts exert negative feedback control on gall bladder emptying in the fasting state without affecting cholecystokinin release or antroduodenal motility.

BACKGROUND: Intraduodenal bile salts exert negative feedback control on postprandial gall bladder emptying. AIMS: We wished to examine whether a similar control mechanism occurs in the fasting state. METHODS: Intraduodenal bile salt depletion was achieved by 12 g of cholestyramine. Thereafter, in study A (seven subjects), the effects on gall bladder volume (by ultrasound) and antroduodenal motility of intraduodenal infusions of taurocholate egg yolk-phosphatidylcholine micelles were assessed. In study B (nine subjects), the effects on gall bladder volume of infusing mixed micelles composed of taurocholate (100 mM) and low (26 mM) or high (68 mM) amounts of egg yolk-phosphatidylcholine, or low amounts of dipalmitoylphosphatidylcholine were determined. RESULTS: Cholestyramine induced strong and prolonged gall bladder contraction without cholecystokinin release. In study A, micellar infusions increased gall bladder volume without affecting migrating motor complex cycle length. In study B, intraduodenal infusion induced strong increases in gall bladder volume in the case of taurocholate micelles containing low amounts of egg yolk-phosphatidylcholine, moderate increases in micelles containing low amounts of dipalmitoylphosphatidylcholine but no change in micelles containing high amounts of egg yolk-phosphatidylcholine, in all cases without altered plasma cholecystokinin levels. Phosphatidylcholine hydrolysis was significantly higher after infusion of egg yolk-phosphatidylcholine compared with infusion of dipalmitoylphosphatidylcholine containing micelles. Intermixed micellar-vesicular bile salt concentrations (responsible for detergent effects) were higher in egg yolk-phosphatidylcholine than in dipalmitoylphosphatidylcholine containing model biles and if lyso-phosphatidylcholine was included. CONCLUSIONS: Intraduodenal bile salts exert negative feedback on fasting gall bladder volume. The modulating effects of various phospholipids may relate to their effects on intermixed micellar-vesicular bile salt concentrations.

Adult↗
PubMed2001

A processing enzyme cleaving avian progastrin at post-Phe bonds.

Neuroendocrine peptides mature partly through endoproteolytic processing of long precursor forms. Best characterised is cleavage at mono- and dibasic residues, but additional sites also exist. Among these is post-Phe cleavage, first suggested to participate in the processing of chicken progastrin. In order to characterise this new mechanism, antibodies recognising the processing products of post-Phe cleavage of chicken progastrin were produced for radioimmunoassay measurements and immunocytochemistry. High concentrations of the carboxyamidated C-terminus and the N-terminus of gastrin-53 were measured in extracts of the antrum. In addition, significant amounts were detected using an assay specific for the N-terminus of gastrin-30 and with another assay for the C-terminus of the corresponding peptide, gastrin-53(1-23), obtained after cleavage at the Phe(23)-Ala(24) bond of gastrin-53. Colocalisation in antral G-cells of the N-termini of gastrin-53 and gastrin-30 and of the C-terminus of gastrin-53(1-23) was confirmed by immunohistochemistry. Finally, we identified the intact N-terminal 1-23 fragment of gastrin-53 complementary to gastrin-30, verifying endoproteolytic cleavage at the Phe(23)-Ala(24) bond. Taken together, the results support the existence of vertebrate endoprotease cleaving hormone precursors at post-Phe sites.

Amino Acid Sequence↗
PubMed2001

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

BACKGROUND: Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall-bladder emptying. AIM: To elucidate the effects of a new long-acting octreotide formulation (Sandostatin LAR) on gall-bladder emptying, cholecystokinin release and gallstone formation. METHODS: Postprandial gall-bladder and gastric emptying were determined by ultrasonography and cholecystokinin release was measured in seven patients on days 0, 14, 28, and 75 (Sandostatin LAR, 20 mg intramuscularly on days 1, 30, and 60). RESULTS: During treatment, fasting gall-bladder volumes increased from 26.5 +/- 3.2 mL to 61.4 +/- 7.5 mL, but postprandial cholecystokinin release and gall-bladder emptying (from 63.9 +/- 3.8% to 12.3 +/- 3.5%) were severely suppressed. Gallstones formed in six out of seven patients within 8 months of treatment. Gastric emptying did not change during the therapy. CONCLUSIONS: The risk of gallstone formation is greatly increased during Sandostatin LAR. This is probably related to profound suppression of cholecystokinin release and gall-bladder emptying.

Acromegaly↗
PubMed2001

Allelic loss of chromosome 2p21-16.3 is associated with reduced survival in sporadic colorectal cancer.

BACKGROUND: Since allelic loss of genes involved in the development of colorectal cancer could serve as prognostic markers, we examined the correlation between loss of markers linked to the hMSH2/hMSH6 (2p21-16.3), hMLH1 (3p21.3), APC (5q21-22), p53 (17p13.1) and DCC (18q21.3) loci and survival in a series of 64 consecutively collected colorectal cancers. METHODS: The association between allelic loss and survival was analysed by univariate and multivariate tests to identify independent variables of survival. RESULTS: Loss of chromosome 2p21-16.3 reduced the overall 5-year survival from 52% to 15% (P = 0.0003). The prognostic significance was evident in patients with Dukes' A + B as well as Dukes' C tumours. A multivariate analysis comparing Dukes' staging, age at diagnosis, tumour localization, sex, loss of chromosome 2p21-16.3, 3p21.3, 5q21-22, 17p13.1 or 18q21.3 and microsatellite instability showed that only Dukes' staging (hazard ratio 3.0; 1.4-6.5 with 95% confidence interval, P = 0.0065) and loss of 2p21-16.3 (hazard ratio 6.2; 2.3-16.8 with 95% confidence interval, P = 0.0006) were independent variables of survival. Loss of 2p21-16.3 was, moreover, associated with increased loss of the other tumour suppressor loci (P = 0.012). CONCLUSIONS: The results show that loss of 2p21-16.3 is an independent indicator of survival in patients with colorectal cancer.

Adenocarcinoma↗