Abnormal Tryptophan Metabolism Research Articles

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism.

BackgroundAutism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of “control” status.MethodsASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2–7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.ResultsUrinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.ConclusionsThe metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18F-FETrp and 11C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. 18F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18F-FETrp showed higher tumoral SUV than 11C-AMT in all 3 tumor types tested. The radiation dosimetry for 18F-FETrp determined from the mouse data compared favorably with the clinical 18F-FDG PET tracer. 18F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

Research Progress on role of Abnormal Tryptophan Metabolism in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a common acquired autoimmune hematological disorders. Platelet autoantibodies lead to the decrease of platelet production and (or) increase of its destruction. The latest researches showed that the abnormal tryptophan metabolism mediated by indoleamine-2, 3-dioxygenase(IDO) is related with the pathogenesis of ITP. The patients with ITP show less expression of IDO, reduction of Treg cells and increase of autoreactive T cells and autoantibodies. CTLA-4-Ig can improve the expression of IDO in the patients with ITP, which also can inhibit the proliferation and activation of self-reactive T cells. Thus, clarifying the abnormal tryptophan metabolism mediated by IDO may provide a new idea for improving the understand of the pathogenesis and treatment of ITP. This review focuses on reasearch progress of the tryptophan metabolism mediated by IDO and ITP.

NIMG-37IMAGING CEREBRAL TRYPTOPHAN METABOLISM IN BRAIN TUMOR-ASSOCIATED DEPRESSION

Background: Depression in patients with brain tumors is associated with impaired quality of life and shorter survival. Altered metabolism of tryptophan to serotonin and kynurenine metabolites may play a role in tumorassociated depression. Our recent studies with alpha[ 11 C]methyl-L-tryptophan (AMT)-PET in brain tumor patients indicated abnormal tryptophan metabolism not only in the tumor mass but also in normal-appearing contralateral brain. In the present study, we explored if tryptophan metabolism in such brain regions is associated with depression. Methods: Twenty-one patients (mean age: 57 years) with a brain tumor (10 meningiomas, 8 gliomas, and 3 brain metastases) underwent AMT-PET scanning. MRI and AMT-PET images were co-registered, and AMT kinetic parameters, including volume of distribution (VD’, an estimate of net tryptophan transport) and K (unidirectional uptake, related to tryptophan metabolism), were measured in the tumor mass and in unaffected cortical and subcortical regions contralateral to the tumor. Depression scores (based on the Beck Depression Inventory-II [BDI-II]) were correlated with tumor size, grade, type, and AMT-PET variables. Results: The mean BDI-II score was 12 ± 10 (range: 2–33); clinical levels of depression were identified in seven patients (33 %). High BDI-II scores were most strongly associated with high thalamic AMT K values both in the whole group (Spearman’s rho = 0.63, p= 0.004) and in the subgroup of 18 primary brain tumors (r= 0.68, p = 0.004). Frontal and striatal VD’ values were higher in the depressed subgroup than in non-depressed patients (p< 0.05); the group difference was even more robust when moderately/severely depressed patients were compared to patients with no/mild depression (frontal: p= 0.005; striatal: p< 0.001). Tumor size, grade, and tumor type were not related to depression scores. Conclusions: Abnormalities of tryptophan transport and metabolism in the thalamus, striatum, and frontal cortex, measured by PET, are associated with depression in patients with brain tumor. These changes may indicate an imbalance between the serotonin and kynurenine pathways and serve as a molecular imaging marker of brain tumor-associated depression. Trial registration: ClinicalTrials.gov NCT02367469

Imaging cerebral tryptophan metabolism in brain tumor-associated depression.

BackgroundDepression in patients with brain tumors is associated with impaired quality of life and shorter survival. Altered metabolism of tryptophan to serotonin and kynurenine metabolites may play a role in tumor-associated depression. Our recent studies with alpha[11C]methyl-L-tryptophan (AMT)-PET in brain tumor patients indicated abnormal tryptophan metabolism not only in the tumor mass but also in normal-appearing contralateral brain. In the present study, we explored if tryptophan metabolism in such brain regions is associated with depression.MethodsTwenty-one patients (mean age: 57 years) with a brain tumor (10 meningiomas, 8 gliomas, and 3 brain metastases) underwent AMT-PET scanning. MRI and AMT-PET images were co-registered, and AMT kinetic parameters, including volume of distribution (VD’, an estimate of net tryptophan transport) and K (unidirectional uptake, related to tryptophan metabolism), were measured in the tumor mass and in unaffected cortical and subcortical regions contralateral to the tumor. Depression scores (based on the Beck Depression Inventory-II [BDI-II]) were correlated with tumor size, grade, type, and AMT-PET variables.ResultsThe mean BDI-II score was 12 ± 10 (range: 2–33); clinical levels of depression were identified in seven patients (33 %). High BDI-II scores were most strongly associated with high thalamic AMT K values both in the whole group (Spearman’s rho = 0.63, p = 0.004) and in the subgroup of 18 primary brain tumors (r = 0.68, p = 0.004). Frontal and striatal VD’ values were higher in the depressed subgroup than in non-depressed patients (p < 0.05); the group difference was even more robust when moderately/severely depressed patients were compared to patients with no/mild depression (frontal: p = 0.005; striatal: p < 0.001). Tumor size, grade, and tumor type were not related to depression scores.ConclusionsAbnormalities of tryptophan transport and metabolism in the thalamus, striatum, and frontal cortex, measured by PET, are associated with depression in patients with brain tumor. These changes may indicate an imbalance between the serotonin and kynurenine pathways and serve as a molecular imaging marker of brain tumor-associated depression.Trial registrationClinicalTrials.gov NCT02367469Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0136-9) contains supplementary material, which is available to authorized users.

Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance.

ABSTRACTTryptophan metabolites have been linked in observational studies with type 2 diabetes, cognitive disorders, inflammation and immune system regulation. A rate-limiting enzyme in tryptophan conversion is arylformamidase (Afmid), and a double knockout of this gene and thymidine kinase (Tk) has been reported to cause renal failure and abnormal immune system regulation. In order to further investigate possible links between abnormal tryptophan catabolism and diabetes and to examine the effect of single Afmid knockout, we have carried out metabolic phenotyping of an exon 2 Afmid gene knockout. These mice exhibit impaired glucose tolerance, although their insulin sensitivity is unchanged in comparison to wild-type animals. This phenotype results from a defect in glucose stimulated insulin secretion and these mice show reduced islet mass with age. No evidence of a renal phenotype was found, suggesting that this published phenotype resulted from loss of Tk expression in the double knockout. However, despite specifically removing only exon 2 of Afmid in our experiments we also observed some reduction of Tk expression, possibly due to a regulatory element in this region. In summary, our findings support a link between abnormal tryptophan metabolism and diabetes and highlight beta cell function for further mechanistic analysis.

The effect of dietary tryptophan levels on oxidative stress of liver induced by diquat in weaned piglets.

Oxidative stress can induce abnormal tryptophan metabolism. The present study was mainly conducted to determine the effect of dietary tryptophan levels on oxidative stress in the liver of weaned pigs challenged by diquat. A total of 36 PIC piglets weaned at 21 days of age were randomly allotted to 1 of 3 diets containing dietary tryptophan levels of 0.18, 0.30, and 0.45% for 14 d. On day 8, the piglets were injected intraperitoneally with sterile 0.9% NaCl solution or diquat (10 mg/kg body weight). During the first 7 d of trial, increasing dietary tryptophan levels enhanced average daily gain (P = 0.09) and average daily feed intake (P = 0.08), and decreased the feed efficiency (P < 0.05) of piglets. The growth performance was decreased by diquat injection (P < 0.05). Diquat injection also decreased the activities of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma and liver (P < 0.05), increased plasma malondialdehyde (MDA) (P < 0.05) and urea nitrogen (P < 0.05) concentrations, and enhanced MDA concentration (P = 0.09) and tryptophan 2,3-dioxygenase (TDO) activity (P = 0.07) in liver of piglets. Increasing dietary tryptophan levels could attenuate the effects of diquat injection on the MDA (P = 0.06) concentration and the activities of SOD (P = 0.09) and GPx (P = 0.05) of the liver, and plasma urea nitrogen (P = 0.06) concentration in the piglet. There was a synergistic role for increasing TDO activity in the liver between dietary tryptophan levels and diquat injection (P < 0.05). These results suggest that increasing dietary tryptophan levels could attenuate the oxidative stress of the liver in weaned piglets intraperitoneally injected with diquat via enhancing the antioxidant capacity.

Effects of Tranilast on the Urinary Excretion of Kynurenic and Quinolinic Acid under Conditions of L Tryptophan Loading

The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3-di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.

Specific Immunotherapy Normalizes Tryptophan Concentrations in Patients with Allergic Rhinitis

Background/Aims: An immune shift towards Th2-type immunity seems to be critical in the pathogenesis of allergic asthma and rhinitis. In a previous study, we found higher serum tryptophan concentrations in patients with seasonal tree or grass pollen rhinoconjunctivitis who underwent specific immunotherapy (SCIT) than in controls, and those with the highest levels at baseline responded less well to SCIT. In the present study, we examined whether ‘booster immunotherapy’ after cessation of SCIT had any influence on tryptophan metabolism during follow-up. Methods: Serum concentrations of tryptophan, kynurenine and neopterin were assayed in 19 patients (mean age: 26.2 years; 6 females) allergic to grass and/or tree pollen before and after they had received a booster immunotherapy with 4 injections of an allergoid vaccine (Pollinex Quattro; Bencard Vienna, Austria) over 8 ± 3 months outside the pollen season. Results: Serum tryptophan and kynurenine concentrations decreased after booster immunotherapy (mean ± SD, before immunotherapy: 81.1 ± 14.2 µmol/l, after immunotherapy: 61.4 ± 20.9 µmol/l and before immunotherapy: 2.25 ± 0.44, after immunotherapy: 1.69 ± 0.70 µmol/l, respectively; both p < 0.01); this was especially true in those responders who also tended to have lower baseline kynurenine concentrations as compared with nonresponders (p = 0.05). Finally, a correlation between changes in tryptophan metabolism and neopterin concentrations was observed after immunotherapy. Conclusions: The decrease in tryptophan and kynurenine concentrations following booster immunotherapy in hay fever patients strengthens the hypothesis that tryptophan metabolism might be involved in the course of allergic responses. However, it is still unclear whether the abnormal tryptophan metabolism in pollinosis patients is related to indoleamine 2,3-dioxygenase and/or to a specific cytokine background.

Metabonomics study of atherosclerosis rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry

An ultra fast liquid chromatography coupled with IT-TOF mass spectrometry (UFLC/MS-IT-TOF) metabonomic approach was employed to study the plasma and urine metabolic profiling of atherosclerosis rats. Acquired data were subjected to principal component analysis (PCA) for differentiating the atherosclerosis and the control groups. Potential biomarkers were screened by using S-plot and were identified by the accurate mass and MSn fragments information obtained from UFLC/MS-IT-TOF analysis. 12 metabolites in rat plasma and 8 metabolites in urine were identified as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcarnitine, butyrylcarnitine, propionylcarnitine and spermine in plasma and 3-O-methyl-dopa, ethyl N2-acetyl-l-argininate, leucylproline, glucuronate, t6A N(6)-(N-threonylcarbonyl)-adenosine and methyl-hippuric acid in urine decreased in atherosclerosis rats. Ursodeoxycholic acid, chenodeoxycholic acid, LPC (C16:0), LPC (C18:0) and LPC (C18:1) in plasma and hippuric acid in urine were in higher levels in atherosclerosis rats. The alterated metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids and amino acids. This research proved that metabonomics is a promising tool for disease research.

α‐[11C]methyl‐L‐tryptophan uptake in patients with periventricular nodular heterotopia and epilepsy

Alpha-[11C]methyl-L-tryptophan (alpha-MTrp) positron emission tomography (PET) is a promising tool in the localization of the epileptogenic area in selected group of focal epilepsy patients. Electrophysiological evidence suggests the involvement of the neocortex in periventricular nodular heterotopia (PVNH). To determine whether alpha-MTrp PET can detect neocortical changes in patients with PVNH. Four patients (2 male, mean age 28, range 23-35 years) with PVNH and intractable seizures were studied. The functional image in each patient was compared with those from 21 healthy controls (mean age 34.6 +/- 14.2 years) by using statistical parametric mapping (SPM). The location of increased alpha-MTrp uptake was compared with the location of the EEG focus. A significant cluster was defined as a cluster with a height p = 0.005 and an extent threshold 100. Alpha-MTrp PET revealed increased cortical uptake in two of four patients. The area of increased alpha-MTrp uptake in one patient was widespread. In the other patient, the area of increased uptake did not include the region where most seizures were generated on EEG. alpha-MTrp PET did not show increased uptake in the heterotopic nodules in any of the patients. Alpha-MTrp PET suggests abnormal metabolism of tryptophan in the neocortex. The increased uptake may be diffuse and may not co-localize with the EEG focus. This preliminary study suggests that alpha-MTrp PET may be useful, in conjunction with other evaluations, in localizing epileptic focus in patients with PVNH and refractory seizures.

Abnormal brain tryptophan metabolism and clinical correlates in Tourette syndrome

Symptoms in Tourette syndrome (TS) are likely related to abnormalities involving multiple neurotransmitter systems in striatal-thalamo-cortical circuitry. Although prior studies have found abnormal levels of tryptophan, serotonin, and their metabolites in blood, cerebrospinal fluid and brain tissue of TS patients, understanding of focal brain disturbances and their relationship to clinical phenotype remains poor. We used alpha-[(11)C]methyl-L-tryptophan (AMT) positron emission tomography (PET) to assess global and focal brain abnormalities of tryptophan metabolism and their relationship to behavioral phenotype in 26 children with TS and nine controls. Group comparisons on regional cortical and subcortical AMT uptake revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P = 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Behaviorally defined subgroups within the TS sample revealed differences in the pattern of AMT uptake in the fronto-striatal-thalamic circuit. This study demonstrates cortical and subcortical abnormalities of tryptophan metabolism in TS and provides neuroimaging evidence for a role of serotonergic mechanisms in the pathophysiology of TS.

Blood 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury

Following a study of oxidative tryptophan metabolism to kynurenines, we have now analysed the blood of patients with either Huntington's disease or traumatic brain injury for levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and melatonin. There were no differences in the baseline levels of these compounds between patients and healthy controls. Tryptophan depletion did not reduce 5-HT levels in either the controls or in the patients with Huntington's disease, but it increased 5-HT levels in patients with brain injury and lowered 5-HIAA in the control and Huntington's disease groups. An oral tryptophan load did not modify 5-HT levels in the patients but increased 5-HT in control subjects. The tryptophan load restored 5-HIAA to baseline levels in controls and patients with brain injury, but not in those with Huntington's disease, in whom 5-HIAA remained significantly depressed. Melatonin levels increased on tryptophan loading in all subjects, with levels in patients with brain injury increasing significantly more than in controls. Baseline levels of neopterin and lipid peroxidation products were higher in patients than in controls. It is concluded that both groups of patients exhibit abnormalities in tryptophan metabolism, which may be related to increased inflammatory status and oxidative stress. Interactions between the kynurenine, 5-HT and melatonin pathways should be considered when interpreting changes of tryptophan metabolism.

In VivoUptake and Metabolism of α-[11C]Methyl-l-Tryptophan in Human Brain Tumors

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. alpha-[(11)C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD') and the metabolic rate constant (k(3)') were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood-brain barrier, while k(3)' values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k(3)'. In contrast, oligodendrogliomas showed high VD' values but lower k(3)' as compared with normal cortex. In astrocytic tumors, low grade was associated with high k(3)' and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Correlation Between Plasma Neurotransmitters and Memory Loss in Pregnancy

More than half of pregnant women believe that their memory becomes impaired, and, indeed, there is evidence from reported studies of objectively impaired memory function. One suggestion is that this is a result of abnormal tryptophan metabolism in pregnancy. The question of whether altered plasma levels of neurotransmitters might be responsible for pregnancy-related memory loss was addressed in 50 healthy pregnant women with an average age of 23, followed from the first trimester of pregnancy. Fifty nonpregnant women with an average age of 23 served as a control group. In addition to memory testing with the Wechsler memory scale, the participants were asked for personal information, tested for orientation, and completed tests requiring backward counting, reading and recalling a paragraph, writing digits forward and backward, and remembering photographs. The pregnant women had significant declines in plasma levels of epinephrine, serotonin, and dopamine in each trimester compared with control women. Plasma norepinephrine, in contrast, increased in the pregnant women. Memory declined significantly in each trimester, the deficit peaking in mid pregnancy. Functional memory correlated positively with levels of epinephrine, serotonin, and dopamine in the second trimester and negatively with plasma serotonin and dopamine levels in the third trimester. Norepinephrine and functional memory correlated negatively in all stages of pregnancy. Functional memory loss was most marked in the second trimester of pregnancy in these healthy women; the loss was minimal in late pregnancy. A decline in plasma neurotransmitter levels may be responsible. Studies of how well women remember parturition and of memory status in the postpartum period would be of interest.

Fructose Malabsorption is Associated with Decreased Plasma Tryptophan

Background: Fructose malabsorption is characterized by the inability to absorb fructose efficiently. As a consequence fructose reaches the colon where it is broken down by bacteria to short fatty acids, CO2, H2, CH4 and lactic acid. Bloating, cramps, osmotic diarrhea and other symptoms of irritable bowel syndrome are the consequence and can be seen in about 50% of fructose malabsorbers. Recently it was found that fructose malabsorption was associated with early signs of depressive disorders. Therefore, it was investigated whether fructose malabsorption is associated with abnormal tryptophan metabolism. Methods: Fifty adults (16 men, 34 women) with gastrointestinal discomfort were analyzed by measuring breath hydrogen concentrations after an oral dose of 50 g fructose after an overnight fast. They were classified as normals or fructose malabsorbers according to their breath H2 concentrations. All patients filled out a Beck depression inventory questionnaire. Blood samples were taken for plasma tryptophan and kynurenine measurements. Results:

Fructose malabsorption is associated with decreased plasma tryptophan.

Fructose malabsorption is characterized by the inability to absorb fructose efficiently. Consequently fructose reaches the colon and is broken down by bacteria to short-fatty-acids, CO2 and H2. Recently we found that fructose malabsorption was associated with signs of depression. It was therefore of interest to find out whether fructose malabsorption is associated with abnormal tryptophan metabolism. Breath hydrogen concentrations were measured in 50 after an oral dose of 50 g fructose allowing to classify them as normals (n = 15) or fructose malabsorbers (n = 35). Blood samples were taken for tryptophan and kynurenine measurements. Fructose malabsorbers showed significantly lower plasma tryptophan concentrations and significantly higher depression scores compared to normals. Fructose malabsorption is associated with lower tryptophan levels which may play a role in the development of depressive disorders.

The role of TLC in the screening of inherited metabolic diseases

Thin-layer chromatography (TLC) is a rapid, reliable and inexpensive screening technique for diagnosis of inherited metabolic diseases (IMD). Our screening program encompasses five main situations where the use of TLC is considered to be vindicated: (i) analysis of amino acids; (ii) screening for sugar defects; (iii) detection of pathological oligosaccharidurias; (iv) screening for organic acid disorders; and (v) detection of abnormalities in tryptophan metabolism. Examples are presented of chromatograms obtained from pathological samples.

The effects of induced kynurenine pathway on immunocytochemical changes in rat tissues following excessive L-tryptophan consumption.

During the past decade it has been reported that diets containing excessive L-tryptophan have caused multisystemic manifestations in humans, known as Eosinophilia Myalgia Syndrome (EMS) (Duffy, 1992). Abnormal metabolism of tryptophan was also reported in clinical syndromes such as carcinoid syndrome (Cooper et al., 1991), scleroderma-like syndrome (Varge et al., 1990; Bruce et al., 1990; Smith et al., 1990), eosinophilic fasciitis (Freis et al., 1973), idiopathic scleroderma (Stenerg et al., 1980) and systemic sclerosis (Freis et al., 1973). Inflammatory responses were elicited in all these syndromes as leukocyte infiltration and fibroblast proliferation were constantly seen in histological sections from lung skin and muscle tissues. It is thus possible that excessive L-tryptophan intake is involved in stimulation of the immune system. However, the mechanism by which tryptophan or its metabolites are involved in these processes is not yet understood. Since it is impossible to precisely follow such effects in humans, it was the purpose of the present study to follow the effects of L- tryptophan and its metabolites in an animal model that demonstrates similar effects to those observed in human tissues.

Neocortical neurotransmitter markers in Huntington's disease.

Several neurotransmitter markers were determined in post mortem tissue from temporal and frontal cortex in Huntington's disease in order to identify and understand the specific neuronal losses that occur in the neocortex in this disease. Decreases in GABA and glutamate concentrations were identified, together with increases in metabolites of dopamine and 5-hydroxytryptamine, indicative of regulatory changes presumably induced by the neuronal deficits. There is also evidence for abnormal cortical tryptophan metabolism. These changes may well contribute to some of the behavioural symptoms of the disease.