Biomedical subjects

S W Lamberts

Publications and source records attributed to S W Lamberts.

At least 19 recordsLinked to original sources

PubMed2003

[Unused knowledge? A useful result of research from the funded Investigative Medicine program].

Many policy-makers believe that the translation of research findings into daily practice is poor. Examples of projects from the research programme 'Investigative medicine' over the period 1990-1995 show that this opinion is not correct. Findings from medical technology assessments that focus on clinical decision making were usually translated into clinical practice very quickly, sometimes even before clinical guidelines had been produced or revised. In almost all cases, the formulation of governance policies concerning the financing and distribution of medical services and interventions required considerably more time.

Health Policy↗

PubMed2001

Internalization-defective mutants of somatostatin receptor subtype 2 exert normal signaling functions in hematopoietic cells.

The regulatory peptide somatostatin (SST) acts via a family of G-protein-coupled receptors comprising five subtypes (SSTR1-5). G-protein-coupled receptors activate multiple signaling mechanisms, which variably depend on internalization and intracellular routing of activated receptors. We have recently demonstrated that hematopoietic precursors express SSTR2 and that SST is a chemoattractant for these cells. Herein, we characterize critical regions in SSTR2 involved in endocytosis and describe how ligand-induced internalization impacts on two major signaling functions of SSTR2 in hematopoietic cells, the activation of the Erk pathway and the induction of promigratory responses.

Amino Acid Sequence↗

PubMed2001

Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.

Alternative Splicing↗

PubMed2001

Neuroendocrine tumor markers.

Tumor markers used in the diagnosis and follow-up of patients with neuroendocrine tumors are in most instances not specific for a given tumor and circulate under normal conditions in the serum, making their use as an early diagnostic tool difficult (low sensitivity). By combining hormone measurements with tissue responsiveness, demonstrations of inappropriate secretions of PTH, insulin, and gastrin during hypercalcemia, hypoglycemia, and hyperacidity, respectively, become highly sensitive and specific diagnostic tests. The application of polyclonal antibodies in RIAs of hormones, such as ACTH, insulin, and gastrin, increase the diagnostic level of hormone measurements in patients with neuroendocrine tumors. Other markers, such as chromogranin A, neuron-specific enolase, and alpha-subunit, as well as peptide receptor visualization, are of increasing importance in the diagnosis and follow-up of neuroendocrine and non-neuroendocrine tumors.

Biomarkers, Tumor↗

PubMed2001

Somatostatin induces migration of acute myeloid leukemia cells via activation of somatostatin receptor subtype 2.

Somatostatin, a neuropeptide with multiple activities, exerts its function via G-coupled membrane receptors. Five somatostatin receptor subtypes, sst1-5, have been identified. We have recently established that somatostatin acts as a chemoattractant on normal hematopoietic progenitor cells. Here, we studied the expression of somatostatin receptors (sst) on leukemic cells from 16 AML patients. Using fluorescent somatostatin (Fluo-SS) in flow cytometry, we found that sst are expressed in variable amounts on primary AML cells. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis and immunochemistry revealed that only sst subtype 2 is expressed by AML cells. Using a two-chamber in vitro migration assay, we show that AML cells migrated towards a gradient of octreotide, a stable synthetic analogue of somatostatin. The degree of migration correlated with the cell surface density of sst2 as measured by Fluo-SS binding. These findings indicate that somatostatin influences trafficking of AML cells, which may have implications for the distribution of AML cells in the body and for clinical applications of somatostatin and analogues thereof in the context of AML.

Bone Marrow Cells↗

PubMed2001

Somatostatin modulates G-CSF-induced but not interleukin-3-induced proliferative responses in myeloid 32D cells via activation of somatostatin receptor subtype 2.

INTRODUCTION: Somatostatin, originally identified as a peptide involved in neurotransmission, functions as an inhibitor of multiple cellular responses, including hormonal secretion and proliferation. Somatostatin acts through activation of G-protein-coupled receptors of which five subtypes have been identified. We have recently established that human CD34/c-kit expressing hematopoietic progenitors and acute myeloid leukemia (AML) cells exclusively express SSTR2. A major mechanism implicated in the antiproliferative action of somatostatin involves activation of the SH2 domain-containing protein tyrosine phosphatase SHP-1. While 0.1-1 x 10(-9) M of somatostatin, or its synthetic stable analog octreotide, can inhibit G-CSF-induced proliferation of AML cells, little or no effects are seen on GM-CSF- or IL-3-induced responses. MATERIALS AND METHODS: To study the mechanisms underlying the antiproliferative responses of myeloblasts to somatostatin, clones of the IL-3-dependent murine cell line 32D that stably express SSTR2 and G-CSF receptors were generated. RESULTS: Similar to AML cells, octreotide inhibited G-CSF-induced but not IL-3-induced proliferative responses of 32D[G-CSF-R/SSTR2] cells. Somatostatin induced SHP-1 activity and inhibited G-CSF-induced, but not IL-3-induced, activation of the signal transducer and activator of transcription proteins STAT3 and STAT5. CONCLUSION: Based on these data and previous results, we propose a model in which recruitment and activation of the tyrosine phosphatase SHP-1 by SSTR2 is involved in the selective negative action of somatostatin on G-CSF-R signaling.

Animals↗

PubMed2001

Somatostatin receptor scintigraphy useful in stage I-II Hodgkin's disease: more extended disease identified.

Somatostatin receptor (SS-R) scintigraphy successfully shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.

Adolescent↗

PubMed2001

Effects of fasting and pegvisomant on the GH-releasing hormone and GH-releasing peptide-6 stimulated growth hormone secretion.

OBJECTIVE: Pegvisomant is a mutated GH molecule which prevents functional dimerization and subsequent activation of the growth hormone receptor. Pegvisomant and fasting both lead to GH resistance. DESIGN AND PATIENTS: We performed a double-blind placebo-controlled cross-over study comparing the effects of pegvisomant and fasting on the GH-releasing hormone (GHRH)- and GH-releasing peptide-6 (GHRP-6)-stimulated GH-release before and after 3 days of fasting in 10 healthy lean male subjects. We also performed a single-arm open label study under nonfasting conditions in five of these subjects. On day 1, in random order, at 0800 h, a GHRP-6 or GHRH test was performed. At 1600 h, a GHRH (if the first test was a GHRP-6 test) or GHRP-6-test (if the first test was a GHRH test) was done. After the second test either pegvisomant (80 mg as a single subcutaneous injection) or placebo was administered. On day 4, GHRP-6 and GHRH tests were performed in the same order as on day 1. During the cross-over study, subjects fasted from 2400 h on day 1 until the end of the study. MEASUREMENTS: During the GH stimulation tests, blood samples were drawn every 15 min from 15 to 120 min. GH was determined in all samples. Total insulin-like growth factor (IGF)-I and free IGF-I were determined from the samples at 0 min only. RESULTS: Three days of fasting alone and pegvisomant alone as well as in combination increased GH concentrations, whereas a decrease in serum-free, but not total, IGF-I concentrations was observed. On day 4, fasting and pegvisomant, either alone or in combination, significantly increased GH concentrations after GHRH compared to baseline. Pegvisomant alone did not increase GH concentrations after GHRP-6 administration. Fasting alone increased GH levels after GHRP-6 administration. The combination of fasting and pegvisomant had a synergistic effect on GH release after GHRP-6. CONCLUSION: These human in vivo data suggest that: (1) circulating free IGF-I, and not total IGF-I, is the major component in the negative feedback on GH secretion; (2) increased pituitary GHRH receptor expression plays a role in the mechanism whereby fasting leads to increased GH concentrations; (3) in vivo, GHRP-6 sensitivity seems to be regulated primarily by metabolic factors and not by changes in GH-IGF-I axis.

Adult↗

PubMed2001

Neuroendocrine aspects of immunolymphoproliferative diseases.

Exchange of information occurs between cells of neuroendocrine and immune systems. Neuroendocrine hormones may modulate lymphoid cell activities, including proliferation and mitogenesis, and immune cells may produce neuropeptides as well. Neuropetide Y is synthesized in B-cell leukaemia lymphoblasts, while substance P immunoreactivity has been detected in neoplastic haematological samples of different types of leukaemias. The presence of receptors for neuropeptides on different animal and human lymphoid cell lines, as well as in several types of animal and human lymphoproliferative diseases has been demonstrated. Species variability in receptor distribution has been shown as well. Receptor expression in immune cells may be regulated by changes in microenvironmental conditions, it may also be related to the activation and/ or proliferation state of cells. Vasoactive intestinal peptides receptors have been detected in myeloma cells, while somatostatin receptors have been first detected in vitro on resting lymphocytes and cells of the monocyte/macrophage lineage, and later on human activated lymphocytes and on lymphoblastic leukaemia cells. Somatostatin receptors have been found in biopsies from patients with malignant lymphomas. Tumor localization in non-Hodgkin lymphomas and Hodgkin's disease can be visualized by in vivo somatostatin receptor scintigraphy, contributing to establish the diagnosis and the stage of the disease. Recently. somatostatin receptors have been in vivo and in vitro detected in human thymic tumors. Although treatment of lymphoproliferative diseases with somatostatin analogs is a little explored field, partial remission was found in patients with low-grade non-Hodgkin lymphoma and cutaneous T-cell lymphoma, and a successful treatment with octreotide has been reported in patients with thymoma. Specific somatostatin receptors present in progenitors of immune cells are not expressed in the mature phenotype, while they can be detected in transformed cell lines. The possibility that this phenomenon is caused by oncogene expression cannot be ruled out. Moreover, preliminary data showed a developmental expression of somatostatin receptors in lymphoid cells, suggesting a potential role for neuropeptide receptors as differentiation markers. Although controlled studies are warranted to investigate the efficacy of the currently available analogs, somatostatinergic compounds may be of interest in the treatment of lymphoproliferative malignancies. A promising approach in refractory patients with somatostatin receptor positive malignant lymphomas may be radionuclide-targeted and cytotoxic analog therapy. These concepts increase the possibility of a wider antitumor treatment with ligands for neuroepeptide receptors than in established 'classic' neuroendocrine tumors.

Cell Differentiation↗

PubMed2001

Somatostatin receptor subtype expression in human tumors.

The presence of functional SSR in tumors has several clinical implications which include the possibility a) to control hormonal hypersecretion and related symptomatology by treatment with SS-analogs, b) to detect SSR positive tumors and their metastases by in vivo SSR scintigraphy, and c) to carry out SSR-targeted radiotherapy using radiolabeled SS-analogs. The majority of SSR positive tumors show a differential expression of somatostatin receptor subtypes, sst2 receptors being the most frequently expressed SSR subtype. The predominant expression of sst2 receptors forms the basis for the successful application of sst2 preferring agonists in the treatment of patients with GH-secreting pituitary adenomas, as well as in patients with carcinoid or islet cell tumors. Sst2 and sst5 receptors appear to be differentially involved in the regulation of normal and tumoral pituitary hormone secretion. Additionally, sst2 receptors are involved in the receptor-mediated internalisation of sst2 preferring radiolabeled SS-analogs. The predominant expression of sst2 receptors in neuroendocrine tumors probably determines the successful application of radio-labeled SS-analogs for the detection of primary tumors and their metastases by SSR scintigraphy. In conclusion, the efficacy of treatment with SS-analogs, the visualisation of SSR-positive tumors, as well as the possibility to carry out SSR-targeted radiotherapy, may very well depend upon the density and subtype of SSR that is expressed by the tumors. Therefore, the characterisation of SSR subtypes in human tumors may have important clinical consequences.

Adenoma↗

PubMed2001

Acute effect of pegvisomant on cardiovascular risk markers in healthy men: implications for the pathogenesis of atherosclerosis in GH deficiency.

Cardiovascular risk is increased in GH deficiency (GHD). GHD adults are frequently abdominally obese and display features of the metabolic syndrome. Otherwise healthy abdominally obese subjects have low GH levels and show features of the metabolic syndrome as well. We investigated in healthy nonobese males the effect of the GH receptor antagonist pegvisomant in different metabolic conditions. This is a model for acute GHD without the alterations in body composition associated with GHD. We compared the effect of pegvisomant with that of placebo before and after 3 d of fasting. In addition, we investigated the effect of pegvisomant under normal, i.e. fed, conditions. Three days of fasting as well as pegvisomant alone decreased serum free IGF-I levels (1.0 +/- 0.15 vs. 0.31 +/- 0.05 ng/ml and 0.86 +/- 0.23 vs. 0.46 +/- 0.23 ng/ml, respectively). Fasting in combination with pegvisomant also decreased serum free IGF-I levels (1.0 +/- 0.15 vs. 0.31 +/- 0.07 ng/ml). Treatment with pegvisomant had no additional influence on the decline of free IGF-I induced by fasting. Pegvisomant alone had no influence on insulin sensitivity. The increase in insulin sensitivity induced by fasting was comparable to the increase in insulin sensitivity induced by fasting combined with pegvisomant. Among serum lipid concentrations, only serum triglycerides increased significantly as a result of pegvisomant alone (1.0 +/- 0.2 vs. 1.6 +/- 0.4 mmol/liter). The changes in lipid concentrations induced by fasting alone or pegvisomant were not different from those induced by pegvisomant alone. von Willebrand factor antigen levels declined significantly under the influence of pegvisomant alone (1.1 +/- 0.07 vs. 0.8 +/- 0.06 U/ml). In conclusion, in different metabolic conditions the GH receptor antagonist pegvisomant induces no significant acute changes in the major risk markers for cardiovascular disease. These data suggest that the secondary metabolic changes, e.g. abdominal obesity or inflammatory factors, that develop as a result of long-standing GHD are of primary importance in the pathogenesis of atherosclerosis in patients with GHD.

Adult↗

PubMed2001

Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance.

The roles of GH and its receptor (GHR) in metabolic control are not yet fully understood. We studied the roles of GH and the GHR using the GHR antagonist pegvisomant for metabolic control of healthy nonobese men in fasting and nonfasting conditions. Ten healthy subjects were enrolled in a double blind, placebo-controlled study on the effects of pegvisomant on GHRH and GH-releasing peptide-6 (GHRP-6)-induced GH secretion before and after 3 days of fasting and under nonfasting conditions (n = 5). Under the condition of GHR blockade by pegvisomant in the nonfasting state, GHRP-6 (1 microg/kg) caused a increase in serum insulin (10.3 +/- 2.1 vs. 81.3 +/- 25.4 mU/L; P < 0.001) and glucose (4.2 +/- 0.3 vs. 6.0 +/- 0.6 mmol/L; P < 0.05) concentrations. In this group, a rapid decrease in serum free fatty acids levels was also observed. These changes were not observed under GHR blockade during fasting or in the absence of pegvisomant. We conclude that although these results were obtained from an acute study, and long-term administration of pegvisomant could render different results, blockade of the GHR in the nonfasting state induces tissue-specific changes in insulin sensitivity, resulting in an increase in glucose and insulin levels (indicating insulin resistance of liver/muscle), but probably also in an increase in lipogenesis (indicating normal insulin sensitivity of adipose tissue). These GHRP-6-mediated changes indicate that low GH bioactivity on the tissue level can induce changes in metabolic control, which are characterized by an increase in fat mass and a decrease in lean body mass. As a mechanism of these GHRP-6-mediated metabolic changes in the nonfasting state, direct nonpituitary-mediated GHRP-6 effects on the gastroentero-hepatic axis seem probable.

Adult↗

PubMed2001

Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient.

We describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size was encountered during treatment with pegvisomant. The patient described did benefit from cotreatment with pegvisomant and octreotide, including decreased GH levels, normalization of serum insulin-like growth factor I concentrations, and improvement of visual field defects.

Acromegaly↗

PubMed2001

Fertility and body composition after laparoscopic bilateral adrenalectomy in a 30-year-old female with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by an inborn defect in the 21-hydroxylase gene (CYP21), leading to virilization of female patients and causing ambiguous genitals in the majority of female infants. Adult women may suffer from loss of libido, irregular or absent cycles, and reduced fertility, despite intensive medical treatment. These problems have stimulated the search for alternative treatment modalities. We present an adult female patient, who was difficult to treat medically and whose clinical situation markedly improved after laparoscopic bilateral adrenalectomy. The procedure was well tolerated and without side effects. Postoperatively the elevated serum progesterone and 17-hydroxyprogesterone levels, as well as the undetectable LH levels, normalized. The procedure resulted in marked clinical improvement. Within 12 months after surgery she lost 11 kg in weight. This weight loss consisted mainly of adipose tissue. Acne disappeared, and she had a regular 4-week menstrual cycle, with progesterone levels that are compatible with a luteal phase. The introduction of laparoscopic techniques may give an impulse to the application of surgical therapy at a larger scale in patients with 21-hydroxylase deficiency who are difficult to treat with adrenal suppression therapy.

17-alpha-Hydroxyprogesterone↗

PubMed2001

[(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas.

Selecting the appropriate approach for resection and follow-up of pheochromocytomas (PCCs) is highly dependent upon reliable localization and exclusion of multifocal, bilateral, or metastatic disease. Metaiodobenzylguanidine (MIBG) scintigraphy was developed for functional localization of catecholamine-secreting tissues. Somatostatin receptor imaging (SRI) has a high sensitivity for localizing head and neck paragangliomas, but studies of intraabdominal PCCs are rare. In this study we review our experience of [(123)I]MIBG and SRI, performed since 1983 and 1989, respectively, in the work-up of primary and recurrent PCCs. Scintigraphic results were correlated with catecholamine secretion, size and site, malignancy, associated tumor syndromes, and morphological features. [(123)I]MIBG scans were performed in a total of 75 patients, in 70 cases before resection of primary PCCs and in 5 cases because of recurrent disease. Ninety-one PCCs were resected. The overall detection rates were 83.3% and 89.8% for PCCs larger than 1.0 cm. Multifocal disease was detected in 4 patients with [(123)I]MIBG. [(123)I]MIBG uptake correlated with greater size of PCC (r = 0.33; P = 0.008) and greater concentration of plasma epinephrine (r = 0.32; P = 0.006). [(123)I]MIBG-negative PCCs (n = 14) had significantly (P = 0.01) smaller diameters than [(123I)]MIBG-positive tumors. Furthermore, [(123)I]MIBG uptake was significantly higher in unilateral (P = 0.02), benign (P = 0.02), sporadic (P = 0.02), intraadrenal (P = 0.02), and capsular invasive (P = 0.03) PCCs than in bilateral, malignant, MEN2A/2B-related, extraadrenal, and noninvasive PCCs, respectively. The detection rate of SRI was only 25% (8 of 32) for primary benign PCCs. In 14 patients metastases occurred, which were effectively visualized with [(123)I]MIBG in 8 of 14 cases. SRI was able to detect metastases in 7 of 8 cases, including 3 [(123)I]MIBG-negative metastatic cases. In addition, [(123)I]MIBG and SRI detected 2 recurrences. In conclusion, [(123)I]MIBG uptake is correlated with the size, epinephrine production, and site of PCCs. Its role in bilateral and MEN2A/2B-related PCCs seems limited. In cases of recurrent elevation of catecholamines, localization of metastases and/or recurrence should be attempted with [(123)I]MIBG scintigraphy. In suspicious metastatic PCCs, SRI might be considered to supplement [(123)I]MIBG scintigraphy.

3-Iodobenzylguanidine↗

PubMed2001

Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy.

OBJECTIVE: Ghrelin stimulates growth hormone (GH) secretion both in vivo and in vitro. Ghrelin is mainly produced in and released from the stomach but it is probably also produced in the hypothalamic arcuate nucleus. Whether pituitary GH release is under the control of ghrelin from the stomach and/or from the arcuate nucleus is not known. Moreover, no data on the feedback of GH on systemic ghrelin concentrations are available. It has recently been suggested that ghrelin may induce obesity. DESIGN: In this study, we addressed the following two questions: a) are circulating ghrelin levels increased in human GH deficiency (GHD), and b) does GH treatment modify ghrelin levels in human GHD? METHODS: The study group consisted of 23 patients with GHD. Eighteen had developed adult-onset GHD and five had developed GHD in their childhood (childhood-onset GHD). Ghrelin was measured with a commercially available radioimmunoassay. All measurements were performed twice, first at baseline, before the start of GH replacement therapy, and then again after one year of therapy. GH doses were adjusted every 3 months, targeting serum total IGF-I levels within the normal gender- and age-related reference values for the healthy population. Maintenance doses were continued once the target serum total IGF-I levels were reached. RESULTS: The sum of skinfolds and body water increased significantly, body fat mass and percentage body fat decreased significantly and body mass index and waist-hip ratio were not significantly changed by one year of GH replacement therapy. Before the start of GH replacement therapy, mean value and range for fasting ghrelin in the studied GHD subjects tended to be lower in comparison with healthy subjects in the control group although the difference did not reach significance (GHD ghrelin mean 67.8 pmol/l, range 37.6-116.3 pmol/l; control mean 83.8 pmol/l, range 35.4-132 pmol/l; P=0.11). One year of GH replacement therapy did not modify circulating ghrelin levels (ghrelin before GH therapy: 67.8 pmol/l, range 37.6-116.3 pmol/l; after GH therapy: 65.3 pmol/l, range 35.8-112.6; P=0.56). CONCLUSIONS: We did not observe elevated ghrelin levels in adult GHD subjects and GH replacement therapy did not modify circulating ghrelin levels, despite significant decreases in body fat mass and percentage body fat. It is conceivable that the lack of ghrelin modifications after long-term GH therapy was due to the reduction of adiposity and insulin on one hand, and increased GH secretion on the other. However, it is still possible that systemic ghrelin is involved in the development of obesity, both in normal and GHD subjects.

Adipose Tissue↗

PubMed2001

A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction.

Evidence is accumulating that low levels of IGF-I play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. We examined the role of a genetic polymorphism in the promoter region of the IGF-I gene in relation to circulating IGF-I levels and growth measured as body height, and we studied the relationship of this polymorphism with type 2 diabetes and myocardial infarction. The relation between the IGF-I polymorphism and body height was assessed in a population-based sample of 900 subjects from the Rotterdam Study. Within each genotype stratum, 50 subjects were randomly selected for a study of the relation of this polymorphism with serum IGF-I levels. To assess the risk for type 2 diabetes, we studied 220 patients and 596 normoglycemic control subjects. For myocardial infarction, 477 patients with evidence of myocardial infarction on electrocardiogram and 808 control subjects were studied. A 192-bp allele was present in 88% of the population, suggesting that this is the wild-type allele from which all other alleles originated. Body height was, on average, 2.7 cm lower (95% CI for difference -4.6 to -0.8 cm, P = 0.004), and serum IGF-I concentrations were 18% lower (95% CI for difference -6.0 to -1.3 mmol/l, P = 0.003) in subjects who did not carry the 192-bp allele. In noncarriers of the 192-bp allele, an increased relative risk for type 2 diabetes (1.7 [95% CI 1.1-2.7]) and for myocardial infarction (1.7 [95% CI 1.1-2.5]) was found. In patients with type 2 diabetes, the relative risk for myocardial infarction in subjects without the 192-bp allele was 3.4 (95% CI 1.1-11.3). Our study suggests that a genetically determined exposure to relatively low IGF-I levels is associated with an increased risk for type 2 diabetes and myocardial infarction.

Aged↗

PubMed2001

Somatostatin receptor scintigraphy in the initial staging of low-grade non-Hodgkin's lymphomas.

UNLABELLED: In this prospective study, somatostatin receptor (SS-R) scintigraphy was compared with conventional staging procedures for the initial staging of patients with low-grade non-Hodgkin's lymphoma (NHL). METHODS: Fifty consecutive untreated patients with low-grade NHL underwent SS-R scintigraphy as part of their initial staging. Planar images were obtained 24 and 48 h after intravenous injection of 220 MBq (111)In-pentetreotide. SPECT images of the upper abdomen were obtained from all patients. SS-R scans were evaluated blindly without knowledge of the results of the conventional staging methods. SS-R scintigraphy findings were compared with the results of physical and radiologic examinations. RESULTS: SS-R scintigraphy findings were positive in 42 of 50 patients (84%). In 10 patients (20%), the SS-R scan revealed new lesions that had not been revealed by conventional staging procedures. These 10 patients were all upgraded to a higher stage. Consequently, the treatment plan would have been altered in 5 patients (10%). However, in 19 patients (38%), lesions apparent after conventional staging methods were missed by SS-R scintigraphy. The sensitivity of SS-R scintigraphy varied from 62% for supradiaphragmatic lesions to 44% for infradiaphragmatic lesions. The specificity of SS-R scintigraphy was high (98%-100%). In comparison with CT scanning and sonography, SS-R scintigraphy is inferior for the visualization of NHL lesions in the thorax and abdomen. CONCLUSION: Although SS-R scintigraphy findings are positive in a large proportion of patients with low-grade NHL, in most patients only part of the lesions can be visualized. Because of the limited sensitivity, we recommend SS-R scintigraphy for initial staging of patients with low-grade NHL only in selected conditions and not for the general work-up.

Female↗