Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma.

INTRODUCTION: Pheochromocytomas and paragangliomas (PPGLs) typically secrete catecholamines and their metabolites (metanephrines [MN] and normetanephrine [NMN]). Catecholamines are synthesized by several enzymes: phenylalanine hydroxylase (encoded by PAH), tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (DDC), dopamine ß-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). MN/NMN secretion varies between anatomical and molecular subgroups. The aim of this study was to assess the correlation between DNA methylation of catecholamine synthesis genes and MN/NMN secretion. METHODS: Gene promoter methylation of PAH, TH, AADC, DBH, and PNMT were extracted and calculated based on publicly available data. Comparisons and correlation analysis were performed between MN ± NMN (MN/NMN), NMN only, and neither/unknown secretion patterns. Methylation levels and MN/NMN patterns were compared by three genetic alteration subgroups: pseudohypoxia (PH), kinase signaling (KS), and others. RESULTS: A total of 178 cases were included. Methylation of PAH CpGs negatively correlated with probability for MN/NMN secretion (p < .05 for all CpGs) and positively with NMN-only secretion. NMN-only secreting tumors had significantly higher promoter methylation of PAH, DBH, and PNMT compared with MN/NMN-secreting tumors. MN/NMN-secreting PPGLs had mainly KS alterations (52.1%), whereas NMN-only PPGLs had PH alterations (41.9%). PPGLs in the PH versus KS group had gene promoter hypermethylation of PAH (p = .002), DBH (p = .02), and PNMT (p = .003). CONCLUSIONS: Promoter methylation of genes encoding catecholamine synthesis enzymes is strongly and inversely correlated with MN/NMN patterns in PPGLs. KS and PH-related tumors have distinct methylation patterns. These results imply that methylation is a key regulatory mechanism of catecholamine synthesis in PPGLs.

Effects of Trilostane on urinary Catecholamines and their metabolites in dogs with Hypercortisolism.

BACKGROUND: Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during trilostane therapy. Urine samples were collected during initial work up and during therapy with trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. RESULTS: Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during trilostane therapy. CONCLUSION: Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during trilostane therapy.

Metanephrine neuroendocrine tumor marker detection by SERS using Au nanoparticle/Au film sandwich architecture.

Neuroendocrine tumors, such as pheochromocytoma or paraganglioma, are dangerous tumors that constitute a potential threat for a large number of patients. Currently, the biochemical diagnosis of neuroendocrine tumors is based on measurement of the direct secretory products of the adrenomedullary-sympathetic system or of their metabolites, such as catecholamines or their metanephrine derivatives, from plasma or urine. The techniques used for analysis of plasma free metanephrines, i.e. high-performance liquid chromatography or high-performance liquid chromatography coupled with mass-spectrometry are technically-demanding and time consuming, which limit their availability. Here we demonstrate a simple, fast and low-cost method for detecting metanephrine by Surface Enhanced Raman Scattering (SERS). The protocol consists in using evaporation-induced self-assembly of gold (Au) nanoparticles incubated with the analyte, on planar gold films. The assembly process produces regions with a dense distribution of both inter-particle gaps and particle-film gaps. Finite-difference time-domain simulations confirm that both kinds of gaps are locations of enhanced electromagnetic fields resulting from inter-particle and particle-film plasmonic coupling, useful for SERS amplification. Metanephrine vibrational bands assignment was performed according to density functional theory calculations. Metanephrine metabolite was detected in liquid at concentration levels lower than previously reported for other similar metabolites. The obtained results demonstrate that the Au nanoparticle/Au film exhibits noticeable SERS amplification of the adsorbed metabolite and can be used in the design of efficient, stable SERS-active substrates for the detection and identification of specific tumor markers.

Catecholamines and their O-methylated metabolites in vitreous humor in hypothermia cases.

PURPOSE: The aim of this study was to assess the diagnostic value of catecholamines and their O-methylated metabolites in vitreous humor samples in identifying antemortem cold exposure and fatal hypothermia in the forensic casework. METHODS: A total of 80 autopsy cases (40 hypothermia fatalities and 40 cases in which hypothermia as the main or contributory cause of death was excluded) were selected for this study. Catecholamines and their O-methylated metabolites were measured in urine and vitreous humor samples collected at autopsy. RESULTS: Urine catecholamine and their O-methylated metabolite concentrations were significantly higher in hypothermia-related deaths. On the other hand, measurements in vitreous humor samples did not reveal statistically significant differences between hypothermia-related deaths and controls. CONCLUSIONS: Globally considered, our findings seem to suggest that, contrary to urine catecholamines and their O-methylated metabolites, vitreous levels of these compounds appear to be of limited value in characterizing human antemortem stress reactions due to cold exposure and can hardly be used in the forensic setting to support the diagnosis of hypothermia.

Diagnostic accuracy of plasma free metanephrines in a seated position compared with 24-hour urinary metanephrines in the investigation of pheochromocytoma.

The aim of this study was to determine the diagnostic efficacy of free metanephrines in plasma samples drawn in the seated position compared with 24-h urinary metanephrines in detecting pheochromocytomas in Asian patients. This prospective study was conducted at Samsung Medical Center between May 2010 and July 2011. The study contained 245 subjects, including 28 patients with histologically-proven pheochromocytoma, 44 with histologically-proven non-pheochromocytoma, 112 controls suspected of having tumors but with negative investigations during two or more years of follow-up, and 45 healthy normotensive volunteers. Plasma-free metanephrines were measured by LC-MS/MS. The cut-off values with optimal sensitivity and specificity for plasma metanephrine and plasma normetanephrine were 0.33 nmol/L and 0.61 nmol/L, respectively. Both the plasma metanephrines measurement and urinary metanephrines measurement had a sensitivity of 96.4% (p = 1.00). However, the urinary metanephrines measurement was significantly more specific than the plasma metanephrines measurement (94.2% vs. 75.6%; p < 0.001). When we applied cut-off values based on BMI, specificity improved from 75.6% to 87.2%, with a comparable gain in sensitivity. From a diagnostic perspective, measurement of free metanephrines in plasma drawn in the seated position is highly sensitive but insufficiently specific when compared with measurement of 24-h urinary fractionated metanephrines. The specificity may be improved by applying cut-off values based on BMI. We suggest that free metanephrines in plasma drawn from seated position can also be used as an initial screening test to ensure that pheochromocytomas are not missed in Asian patients.

Proteinuria in metastatic pheochromocytoma is associated with an increased risk of Acute Respiratory Distress Syndrome, spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG).

Acute Respiratory Distress Syndrome (ARDS) has been reported rarely in pheochromocytoma, occurring spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG). Our objective was to determine whether proteinuria is associated with an increased risk of ARDS. This was a retrospective analysis of a prospective cohort study of 64 patients with metastatic pheochromocytoma or paraganglioma treated with 131I-MIBG on institutional protocols. Proteinuria was defined as at least one urinalysis positive for at least trace protein within 1 month prior to 131I-MIBG or within 1 month prior to spontaneous ARDS. Proportions were compared using Fisher's exact test. Urinalyses within the defined time period were available for 48 patients, 8 of whom had proteinuria. Of the 8 patients with proteinuria, 5 developed ARDS: 3 within 10 days following 131I-MIBG, two 6 months following 131I-MIBG. Both patients who developed ARDS 6 months after 131I-MIBG had proteinuria within 1 month before apparently spontaneous ARDS. None of the 40 patients whose urinalyses were all negative for protein developed ARDS. None of the 16 patients with missing urinalyses developed ARDS. Patients with antecedent proteinuria were more likely to develop ARDS than those without proteinuria (63% vs. 0%; p<0.0001). The following variables were not significantly associated with ARDS: 131I-MIBG activities administered, number of 131I-MIBG administrations, age, hypertension, or secretion of catecholamines or metanephrines. In patients with metastatic pheochromocytoma or paraganglioma, proteinuria is associated with ARDS and urine protein should be examined prior to administering 131I-MIBG.

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension.

Introduction: Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO. Method: Catecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting. Results: Plasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation. Conclusion: The low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.

Predictive factors for malignant pheochromocytoma: analysis of 136 patients.

PURPOSE: We evaluated the clinical characteristic, tumor feature and immunohistochemistry factors predicting malignant pheochromocytoma. MATERIALS AND METHODS: Between January 1999 and December 2008 we retrospectively reviewed the records of 136 patients with pheochromocytoma at Ruijin Hospital. We compared clinical characteristics (age, gender, symptoms and biochemical analysis), tumor features (site, weight and diameter) and the expression of 3 angiogenesis/metastasis related genes (VEGF, Cox-2 and MVD) by immunohistochemical analysis of benign vs malignant pheochromocytomas. RESULTS: Of the 136 patients 105 (77%) had benign and 31 (23%) had malignant pheochromocytoma. Malignant tumors were larger and heavier than benign tumors, and accompanied by higher plasma metanephrine secretion (each p <0.001). Mean tumor catecholamine and preoperative 24-hour urinary metanephrine or normetanephrine were obviously higher in malignant than in benign tumors (p <0.001). Also, 25 malignant tumors (81%) were immunopositive for VEGF while only 24 benign tumors (23%) showed this characteristic (p <0.001). Microvessel density and the rate of positive staining for Cox-2 protein in malignant samples were higher than in benign samples (p <0.001). CONCLUSIONS: Several promising predictive parameters are currently available to distinguish benign from malignant pheochromocytoma. Large (5 cm or greater) or heavy (250 gm or greater) tumors, multifocal and extra-adrenal tumors, early onset postoperative hypertension and higher plasma or urine metadrenaline are high risk factors predictive of malignant pheochromocytoma. Also, expression of the 3 angiogenesis or metastasis related genes VEGF, Cox-2 and MVD helps determine the diagnosis of malignancy and suggests strict followup.

Decrease in Salivary Serotonin in Response to Probiotic Supplementation With Saccharomyces boulardii in Healthy Volunteers Under Psychological Stress: Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Bacterial probiotics are thought to exert a serotonergic effect relevant to their potential antidepressant and pro-cognitive action, but yeast probiotics have not been tested. The aim of the present study was to determine whether 30-day supplementation with Saccharomyces boulardii affects the level of salivary serotonin under psychological stress and identify the factors associated with it. Methods: Healthy medical students were randomized to ingest Saccharomyces boulardii CNCM I-1079 or placebo before a stressful event. Salivary serotonin concentration was assessed before and at the end of supplementation. Moreover, obtained results were compared to psychological, biochemical, physiological and sociodemographic study participants data. Results: Data of thirty-two participants (22.8 ± 1.7 years of age, 16 males) was available for the main analysis. Supplementation with Saccharomyces boulardii decreased salivary serotonin concentration under psychological stress by 3.13 (95% CI 0.20 to 6.07) ng/mL, p = 0.037, as compared to placebo. Salivary serotonin was positively correlated with salivary metanephrine (ß = 0.27, 95% CI 0.02 to 0.52, p = 0.031) and pulse rate (ß = 0.28, 95% CI 0.05 to 0.50, p = 0.018), but insignificantly with anxiety, depression, eating attitudes and information retrieval. Conclusions: Saccharomyces boulardii CNCM I-1079 may be distinct from bacterial probiotics in its salivary serotonergic effect, which appears positively linked to symapathoadrenal markers. The study requires cautious interpretation, and further investigation.

A 3-min UPLC-MS/MS method for the simultaneous determination of plasma catecholamines and their metabolites: Method verification and diagnostic efficiency.

OBJECTIVE: To verify a rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of catecholamines and their metabolites, and to validate its efficiency for the diagnosis of phaeochromocytomas and paragangliomas (PPGLs). METHODS: Plasma samples were pretreated with solid-phase extraction, followed by a 3-min UPLC-MS/MS analysis to quantify epinephrine (E), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN) and 3-methoxytyramine (3-MT), simultaneously. The UPLC-MS/MS method was comprehensively verified and its diagnostic efficiency on PPGLs was tested using 7 PPGLs and 408 non-PPGLs patient plasma samples. RESULTS: Using the developed method, the limit of detections (LODs) of the 6 analytes ranged from 0.0002 nmol/L (MN) to 0.0250 nmol/L (NE), while the lower limit of measuring intervals (LLMIs) ranged from 0.05 nmol/L (E, MN and NMN) to 0.10 nmol/L (NE and DA). The reportable ranges were 0.05-30.00 nmol/L for E, MN and NMN, 0.10-30.00 nmol/L for NE and DA, 1.00-300.00 pg/mL for 3-MT. No significant matrix effect was detected after correcting using internal standard. Besides, intra-day and inter-day precision were also within acceptance criteria with coefficient of variations (CVs) ≤ 15% and recoveries ranged from 95% to 115% for all the 6 analytes. The carryover effect was lower than 10%. Its diagnostic efficiency for PPGLs was significantly increased, the areas under the receiver operating characteristic (ROC) curves were increased from 68.7% to 89.1% (using E, NE and DA) to 75.2%-99.9% (using MN, NMN and 3-MT). CONCLUSION: This study verified a rapid UPLC-MS/MS method for the determination of catecholamines and their metabolites in human plasma. It showed high diagnostic efficiency and will serve as an important tool to avoid the risk for missing patients with PPGLs.

Influence of various confounding variables and storage conditions on metanephrine and normetanephrine levels in plasma.

OBJECTIVE: Measurements of plasma free metanephrines have been advocated as first-line tests for phaeochromocytoma. The aim of the study was to assess the impact of potential confounding variables. DESIGN: Comparative study between 2008 and 2009. SUBJECTS: Hundred and eighty healthy subjects. MEASUREMENTS: The effects of age, BMI, gender, menstrual cycle (sampling every 2 days), time of day (sampling every 2 h), venepunture (0, 15, 30, 60, 90 and 120 min), physical exercise (0, 15 and 30 min), coffee (0 and 60 min), breakfast (0 and 60 min) and various body positions (standing and supine rest, each 0 and 120 min) were evaluated. In addition, whole blood and plasma samples were stored at 4 degrees C or at 22 degrees C for 0, 1, 3, 24 and 72 h. Plasma free metanephrines were measured using radioimmunoassay (LDN). RESULTS: While metanephrine was significantly influenced by sex and age, BMI and sex were significant predictors of normetanephrine. Coffee (+20%) and food (+8%) elevated normetanephrine significantly (P < 0.05), while metanephrine remained stable. Physical exercise increased metanephrine (+82%) as well as normetanephrine (+84%) significantly (P < 0.005). Supine rest significantly decreased both metanephrine (-34%) and normetanephrine (-19%) when compared to standing rest (P < 0.01). Metanephrine and normetanephrine were not significantly influenced by time of day, menstrual cycle or venepuncture. When plasma samples were stored at 4 degrees C, metanephrine and normetanephrine were stable for 72 h. CONCLUSIONS: Physical exercise may lead to relevant changes in metanephrine and normetanephrine and should therefore be avoided prior to sampling. Although effects of age, sex and BMI were small, these variables should be considered when interpreting biochemical results. Blood should be taken in the supine position, and samples should be immediately centrifuged and stored at 4 degrees C to improve stability.

The effects of illness on urinary catecholamines and their metabolites in dogs.

BACKGROUND: Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines currently are unknown. OBJECTIVES: To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. ANIMALS: Twenty-five critically ill dogs and 25 healthy age- and sex-matched control dogs. METHODS: Prospective observational study. Urine was collected from healthy and critically ill dogs, and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography with electrochemical detection. Urinary catecholamine and metanephrine:creatinine ratios were calculated and compared between groups. RESULTS: Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine:creatinine ratios were higher in critically ill dogs when compared with a healthy control population (P=.0009, P<0.0001, P<0.0001, and P<0.0001, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool; however, the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness.

Autoimmune Voltage-Gated Potassium Channelopathy Presenting With Catecholamine Excess.

BACKGROUND: Autoimmune voltage-gated potassium channelopathies have been associated with a range of neurological presenting symptoms, including central, peripheral, and autonomic dysfunction. PATIENT DESCRIPTION: We describe a 12-year-old boy who presented with nine months of pain, anxiety, and 30-pound weight loss. He was admitted for failure to thrive, then noted to be persistently hypertensive and tachycardic. Plasma metanephrines and urine metanephrines and catecholamines were elevated. Extensive investigation for causes of elevated catecholamines, such as hyperthyroidism or catecholamine-secreting tumor, was negative. A paraneoplastic panel was positive for voltage-gated potassium channel antibodies. Treatment with intravenous immunoglobulin and pulse methylprednisolone led to complete resolution of symptoms, weight gain, and normalization of vital signs and plasma metanephrines. CONCLUSION: Voltage-gated potassium channel antibodies should be considered as part of the differential in patients presenting with elevated metanephrine and catecholamine secretion.

Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels.

AIM: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine. METHODS: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N1-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N1-methyl-2-pyridone-5-carboxamide during the test period were examined. RESULTS: The level of 3-h plasma nicotinamide, N1-methylnicotinamide, homocysteine, the urinary excretion of N1-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N1-methylnicotinamide (1.90 ± 0.20 µmol/l vs. 3.62 ± 0.27 µmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 µmol/l vs. 18.08 ± 1.02 µmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 µmol/l vs. 23.52 ± 0.61 µmol/l, P < 0.05) than that of the NM group. CONCLUSION: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification.

Mass spectrometric quantification of salivary metanephrines-A study in healthy subjects.

BACKGROUND: Determination of metanephrine (MN), normetanephrine (NMN), and 3-methoxytyramine (3-MT) in saliva may offer potential diagnostic advantages in diagnosing pheochromocytoma. METHODS: In this preliminary study, we determined metanephrine concentrations in saliva of healthy subjects and the relationship with simultaneously measured plasma metanephrines. We also studied the possible influence of pre-analytical conditions such as a collection device, awakening, posture, and eating on the salivary metanephrine levels. RESULTS: Eleven healthy subjects were included. Fasting blood and saliva samples were collected in seated position and after 30min of horizontal rest. Plasma and salivary MN, NMN, and 3-MT concentrations were determined using a high-performance liquid chromatography tandem mass spectrometric technique (LC-MS/MS) with automated solid phase extraction sample preparation. Metanephrines were detectable in saliva from all participants both in seated and supine position. No significant correlations were observed between the MN, NMN, and 3-MT concentrations in saliva and plasma in seated or supine position. Furthermore, there was no difference between MN, NMN, and 3-MT samples collected with or without a collection device. CONCLUSION: Metanephrines can be detected in saliva with LC-MS/MS with sufficient sensitivity and precision. Our findings warrant evaluation of salivary metanephrine measurement as a novel laboratory tool in the work-up of patients suspected of having a pheochromocytoma.

Biogenic amines and depression. Biochemical and pharmacological separation of two types of depression.

Recent research findings indicate that depressive disorders may be divided into two groups, A and B, using specific biochemical and pharmacological criteria. It is suggested that in the A group there is a disorder of norepinephrine systems are not altered. Further, there is the possibility that B types patients have disorder of serotonin, but not norepinephrine or dopamine systems. This biochemical heterogeneity of human depression has implications for both investigators and clinicians, and may account for disparate findings in biological studies of patients with affective disorders.

Catecholamine metabolism and disposition in healthy and depressed subjects.

Depressed patients as a group have been found to excrete greater amounts of catecholamines (CAs) and metabolites than healthy control subjects, but these differences were not uniform for all metabolites. Patients may differ from controls in the metabolism and/or disposition of CAs. We analyzed the suggested metabolic-dispositional differences by determining 24-hour urine values for norepinephrine (NE), epinephrine (E), normetanephrine (NM), metanephrine (M), vanillylmandelic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). For each subject, we calculated ratios of CAs or metabolites to an estimate of CA synthesis and determined ratios of CAs and metabolites to each other based on a precursor-product paradigm. The results indicate that as a group, patients have modestly but significantly greater CA synthesis rates than controls; patients excrete disproportionately more NE and E and disproportionately less MHPG relative to estimated CA synthesis, as well as other metabolites, than do controls; in contrast to NE, E, and MHPG, the increased NM, M, and VMA excretion rates by patients are proportional to each other as well as to the increase in CA synthesis; and the differences in NE, E, and metabolite excretion in the patients as a group are due principally to unipolar rather than bipolar depressives. The differences would be expected if patients, relative to controls, released more NE and E into the circulation. These data indicate the need to measure several CAs and metabolites when evaluating differences between groups since the significance of any given metabolite value needs to be examined in the context of total CA and metabolite production and excretion.

Lithium carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites and treatment outcome.

Treatment of manic patients with lithium carbonate was associated with significant decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary norepinephrine excretion. These measures, before treatment, were higher in manic patients than in either depressed or normal subjects and correlated significantly with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic acid did not correlate with severity or with change during lithium carbonate treatment. Responders (about 70% of the patients) did not differ from nonresponders in pretreatment mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine excretion were reduced during lithium carbonate treatment in both responders and nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher during treatment in nonresponders than in responders and correlated with several indexes of symptom severity. These results support a relationship between mania and increased noradrenergic function. Treatment outcome, however, was not related exclusively to the reduction of noradrenergic indexes by lithium carbonate since reductions were similar in both responders and nonresponders. Reduced noradrenergic activity may therefore be necessary but not sufficient for successful outcome during lithium carbonate treatment.

Angiotensin II status and sympathetic activation among hypertensive patients in Uganda: a cross-sectional study.

BACKGROUND: Sympathetic activation and renin-angiotensin system are essential for development and sustenance of hypertension. However, the status of these systems has not been well evaluated among patients in an African setting. This study therefore set out to assess the angiotensin II status and sympathetic activation among hypertensive patients in Uganda. METHODS: In this cross sectional study conducted at Mulago, the national referral hospital, blood samples were taken to measure angiotensin II, metanephrines and normetanephrines. Urine samples were also taken for measuring urine creatinine and sodium. The angiotensin II categories were defined using the Mosby's Diagnostic and Laboratory Test References. 9th ed while the metanephrines and normetanephrine categories were defined using the Makerere University Biosafety II Immunology Laboratory reference values. RESULTS: 162 patients were consented and enrolled into the study, of these 136 (84 %) had low, 15 (9 %) had normal, while, 11 (7 %) had high angiotensin II levels. 142 (88 %) participants had normal levels of metanephrine, while 20 (12 %) had high levels. Only 88 were assessed for metanephrines and of these 85 (97 %) had normal, while 3 (3 %) had raised levels. Urine sodium was associated with low and normal angiotensin II levels (P value 0.007). Female gender and diastolic blood pressure were associated with a protective effect against high normetanephrines (OR 0.29, P value 0.015), 80-89 mmHg (OR 0.19, p value 0.053), above 100 mmHg (OR 0.27, p value 0.022). Current smoking status was associated with high risk for abnormal normetanephrines (OR 17.6, P value -0.022) while former smoking was associated with high risk for abnormal metanephrines (OR 18.7, p value 0.022). After multivariate analysis, all the significant variables at bivariate analysis were still significant except those who stopped smoking and those with a BP at 80-89 which were not significant. CONCLUSIONS: Hypertensive patients in this setting have predominantly low angiotensin II hypertension as a result of high salt intake. Sympathetic activation is not a significant mechanism of hypertension in this study population, more so in the females, with the exception of smokers who have a highly activated sympathetic system. Therefore, the use of agents targeting renin angiotensin and sympathetic systems as single first line antihypertensive agents in this setting should be re-evaluated if such patients are to be treated effectively.