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author:("kemp, Ido P.")
1.  Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour 
Purpose
Positron emission tomography (PET) using 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers.
Methods
Seventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers.
Results
All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A.
Conclusion
Tumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity.
doi:10.1007/s00259-011-1862-5
PMCID: PMC3168742  PMID: 21698413
18F-dopa PET; Carcinoid tumour; Whole-body metabolic tumour burden; 5-HIAA
2.  Long-range Neural and Gap Junction Protein-mediated Cues Control Polarity During Planarian Regeneration 
Developmental biology  2009;339(1):188-199.
SUMMARY
Having the ability to coordinate the behavior of stem cells to induce regeneration of specific large-scale structures would have far reaching consequences in the treatment of degenerative diseases, acute injury, and aging. Thus, identifying and learning to manipulate the sequential steps that determine the fate of new tissue within the overall morphogenetic program of the organism is fundamental. We identified novel early signals, mediated by the central nervous system and 3 innexin proteins, which determine the fate and axial polarity of regenerated tissue in planarians. Modulation of gap junction-dependent and neural signals specifically induces ectopic anterior regeneration blastemas in posterior and lateral wounds. These ectopic anterior blastemas differentiate new brains that establish permanent primary axes re-established during subsequent rounds of unperturbed regeneration. These data reveal powerful novel controls of pattern formation and suggest a constructive model linking nervous inputs and polarity determination in early stages of regeneration.
doi:10.1016/j.ydbio.2009.12.012
PMCID: PMC2823934  PMID: 20026026
gap junctions; neural signals; regeneration; polarity; planaria
3.  Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications 
The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain.
doi:10.1007/s00259-010-1663-2
PMCID: PMC3034914  PMID: 21113591
Serotonin; Positron Emission Tomography; [11C]5-HTP; [11C]AMT; Depression
4.  Automated mass spectrometric analysis of urinary and plasma serotonin 
Analytical and Bioanalytical Chemistry  2010;396(7):2609-2616.
Serotonin emerges as crucial neurotransmitter and hormone in a growing number of different physiologic processes. Besides extensive serotonin production previously noted in patients with metastatic carcinoid tumors, serotonin now is implicated in liver cell regeneration and bone formation. The aim was to develop a rapid, sensitive, and highly selective automated on-line solid-phase extraction method coupled to high-performance liquid chromatography–tandem mass spectrometry (XLC-MS/MS) to quantify low serotonin concentrations in matrices such as platelet-poor plasma and urine. Fifty microliters plasma or 2.5 μL urine equivalent were pre-purified by automated on-line solid-phase extraction, using weak cation exchange. Chromatography of serotonin and its deuterated internal standard was performed with hydrophilic interaction chromatography. Mass spectrometric detection was operated in multiple reaction monitoring mode using a quadrupole tandem mass spectrometer with positive electrospray ionization. Serotonin concentrations were determined in platelet-poor plasma of metastatic carcinoid patients (n = 23) and healthy controls (n = 22). Urinary reference intervals were set by analyzing 24-h urine collections of 120 healthy subjects. Total run-time was 6 min. Intra- and inter-assay analytical variation were <10%. Linearity in the 0–7300 μmol/L calibration range was excellent (R2 > 0.99). Quantification limits were 30 and 0.9 nmol/L in urine and plasma, respectively. Platelet-poor serotonin concentrations in metastatic carcinoid patients were significantly higher than in controls. The urinary reference interval was 10–78 μmol/mol creatinine. Serotonin analysis with sensitive and specific XLC-MS/MS overcomes limitations of conventional HPLC. This enables accurate quantification of serotonin for both routine diagnostic procedures and research in serotonin-related disorders.
doi:10.1007/s00216-010-3466-5
PMCID: PMC2841759  PMID: 20140664
Serotonin; 5-hydroxytryptamine; LC-MS/MS; On-line SPE; Mass spectrometry; Automation
5.  Investigating the Molecular basis of Major Depressive Disorder etiology: a Functional Convergent Genetic Approach 
Genes play a major role in behavioral adaptation to challenging environmental stimuli, but the complexity of their contribution remains unclear. There is growing evidence linking disease phenotypes with genes on the one hand, and the genesis of stress related disorders like major depression, as a result of exposure to stressful environmental pathogens on the other. Here we illustrate the convergent role of monoaminergic genes in regulating the underlying biological mechanisms of stress and the emotions. By reviewing data that supports a role of monoaminergic and other related genes in environmental adaptation, we concluded by advocating the use of convergent approaches in examining the genetic modulation of disease phenotypes.
doi:10.1196/annals.1410.018
PMCID: PMC2614701  PMID: 19120090
Stress; Genes; Monoamines; MDD; Convergent
6.  Quick identification of acute chest pain patients study (QICS) 
Background
Patients with acute chest pain are often referred to the emergency ward and extensively investigated. Investigations are costly and could induce unnecessary complications, especially with invasive diagnostics. Nevertheless, chest pain patients have high mortalities. Fast identification of high-risk patients is crucial. Therefore several strategies have been developed including specific symptoms, signs, laboratory measurements, and imaging.
Methods/Design
The Quick Identification of acute Chest pain Study (QICS) will investigate whether a combined use of specific symptoms and signs, electrocardiography, routine and new laboratory measures, adjunctive imaging including electron beam (EBT) computed tomography (CT) and contrast multislice CT (MSCT) will have a high diagnostic yield for patients with acute chest pain. All patients will be investigated according a standardized protocol in the Emergency Department. Serum and plasma will be frozen for future analysis for a wide range of biomarkers at a later time point. The primary endpoint is the safe recognition of low-risk chest pain patients directly at presentation. Secondary endpoint is the identification of a wide range of sensitive predictive clinical markers, chemical biomarkers and radiological markers in acute chest pain patients. Chemical biomarkers will be compared to quantitative CT measurements of coronary atherosclerosis as a surrogate endpoint. Chemical biomarkers will also be compared in head to head comparison and for their additional value.
Discussion
This will be a very extensive investigation of a wide range of risk predictors in acute chest pain patients. New reliable fast and cheap diagnostic algorithm resulting from the test results might improve chest pain patients' prognosis, and reduce unnecessary costs and diagnostic complications.
doi:10.1186/1471-2261-9-24
PMCID: PMC2704169  PMID: 19527487
7.  Brief Report: Normal Intestinal Permeability at Elevated Platelet Serotonin Levels in a Subgroup of Children with Pervasive Developmental Disorders in Curaçao (The Netherlands Antilles) 
This study investigated the relationship between platelet (PLT) serotonin (5-HT) and intestinal permeability in children with pervasive developmental disorders (PDD). Differential sugar absorption and PLT 5-HT were determined in 23 children with PDD. PLT 5-HT (2.0–7.1 nmol/109 PLT) was elevated in 4/23 patients. None exhibited elevated intestinal permeability (lactulose/mannitol ratio: 0.008–0.035 mol/mol). PLT 5-HT did not correlate with intestinal permeability or GI tract complaints. PLT 5-HT correlated with 24 h urinary 5-hydroxyindoleacetic acid (5-HIAA; p = .034). Also urinary 5-HIAA and urinary 5-HT were interrelated (p = .005). A link between hyperserotonemia and increased intestinal permeability remained unsupported. Increased PLT 5-HT in PDD is likely to derive from increased PLT exposure to 5-HT. Longitudinal studies, showing the (in)consistency of abnormal intestinal permeability and PLT 5-HT, may resolve present discrepancies in the literature.
doi:10.1007/s10803-007-0399-8
PMCID: PMC2226079  PMID: 17661166
Child development disorders; Pervasive; Platelets; Serotonin; Gastrointestinal; Permeability
8.  Vitamin K Intake and Plasma Desphospho-Uncarboxylated Matrix Gla-Protein Levels in Kidney Transplant Recipients 
PLoS ONE  2012;7(10):e47991.
Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n = 60) with stable renal function (creatinine clearance 61 [42–77] (median [interquartile range]) ml/min), who were 75 [35–188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p = 0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.
doi:10.1371/journal.pone.0047991
PMCID: PMC3485347  PMID: 23118917

Results 1-8 (8)