M. Rebecca Fokkema

Tryptophan as a link between psychopathology and somatic states

Objective: Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon. Methods: We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms “tryptophan” and “serotonin.” Results: The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased. Conclusions: It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.

Increased Intima-Media Thickness After Early-Onset Preeclampsia

OBJECTIVE: Preeclampsia is associated with cardiovascular atherosclerotic events later in life. However, little is known about earlier subclinical signs of atherosclerosis. We aimed to investigate whether women who recently had preeclampsia show increased intima-media thickness (IMT), as marker of early atherosclerosis, compared with women with normal pregnancies or nulliparous women. METHODS: Intima-media thickness of carotid and femoral arteries measured by ultrasonography, and possible confounding risk factors as body mass index, blood pressure, serum lipids, smoking status, and family history of cardiovascular disease were compared among 22 nulliparous women, 22 primiparous women with normal pregnancy, and 22 primiparous women with early-onset preeclampsia at least 3 months postpartum and 6 weeks after ending lactation RESULTS: Except for slightly higher values for blood pressure, triglycerides, and homocysteine in the formerly preeclamptic women, no other clinical or biochemical differences were observed. The preeclampsia group showed an increased IMT (mean ± standard deviation, 0.63 ± 0.14 mm) of the common femoral artery compared with the normal pregnancy group (0.55 ± 0.06 mm, P = .005) and to the nulliparous group (0.52 ± 0.06 mm, P < .001). These differences remained significant after correction for possible confounders by multiple linear regression analyses. An increase in IMT of the common carotid artery between the normal pregnancy and the nulliparous group was observed, which became significant after adjustment for confounders. CONCLUSION: Preeclampsia and, to a lesser degree, normal pregnancy are associated with increased IMT. The association between increased IMT and (preeclamptic) pregnancy leads to the question of which comes first, which should be addressed in follow-up studies. LEVEL OF EVIDENCE: II-2

HbA1c measurements from dried blood spots: validation and patient satisfaction

Abstract Background: This study evaluates HbA1c measurements from dried blood spots collected on filter paper and compares HbA1c from filter paper (capillary blood) with HbA1c measured in venous blood. Methods: Patient satisfaction was evaluated using a questionnaire. The performance with the filter paper method was assessed by comparing HbA1c results from EDTA-blood samples obtained via dried blood spots with HbA1c results obtained with freshly hemolyzed blood (routine HbA1c). Adult patients visiting the outpatient clinic for HbA1c analyses were recruited for the evaluation of dried blood spot sampling at home. Laboratory personnel collected a capillary blood sample on filter paper as well as a venous EDTA-blood sample. The participants collected another capillary blood sample at home and sent the dried filter paper back to the laboratory. Samples were analyzed with an immunoturbidimetric assay. Results: Between-filter coefficient of variation was 1.8%. Filter paper HbA1c increased slightly during storage, particularly during the first 5 days. Filter paper HbA1c highly correlated with routine HbA1c (r=0.987). The evaluation of samples collected at home showed comparable HbA1c values by filter paper and routine sampling methods (n=93). Eighty-three percent of participants said they would like the filter method to be brought into practice. Conclusions: Home HbA1c sampling on filter paper is an acceptable sampling alternative for analysis of HbA1c. Clin Chem Lab Med 2009;47:1259–64.

Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages

UNLABELLED Homocysteine (Hcy) and in particular methylmalonic acid (MMA) are considered reliable parameters for vitamin B(12) status in healthy individuals. Phenylketonuria (PKU) patients are at risk for functional vitamin B(12) deficiency based on their diet. OBJECTIVE The aim of this study was to investigate the prevalence of functional vitamin B(12) deficiency in continuously treated PKU patients and the association of parameters of vitamin B(12) and metabolic control. METHODS In 75 continuously treated PKU patients of 1-37 years of age, serum vitamin B(12) concentrations, plasma Hcy, MMA, and phenylalanine concentrations were studied. RESULTS Eight patients had vitamin B(12) concentrations below normal. Out of these eight patients, two had elevated MMA and/or Hcy concentrations. Ten other patients with normal vitamin B(12) concentrations had elevated concentrations of MMA and/or Hcy. CONCLUSIONS A vitamin B(12) concentration within the reference range does not automatically imply a sufficient vitamin B(12) status. We recommend measuring serum MMA, or alternatively plasma Hcy, yearly in all PKU patients to diagnose functional vitamin B(12) deficiency.

Fasting vs Nonfasting Plasma Homocysteine Concentrations for Diagnosis of Hyperhomocysteinemia

Hyperhomocysteinemia, a risk factor for cardiovascular and thrombotic disease, pregnancy complications, and cognitive disorders, is defined as a fasting plasma total Hcy (tHcy) above a chosen cutoff value (1)(2). Reducing both the analytical and biological variation may add to the diagnostic value of any test. tHcy analytical variation (CVa) is method-dependent and ranges from 2.7% to 4.9% for fluorescence polarization immunoassays and from 2.5% to 14% for HPLC assays (3). The reported biological variations for tHcy under fasting or otherwise standardized conditions include 20–34% interindividual variation (CVg) and 7–11% (with a single extreme of 15–17%) intraindividual variation (CVi) (4)(5)(6)(7)(8)(9). Because of the short-term influence of meals, e.g., protein, on CVi (10), it is generally recommended that blood samples be collected under fasting or otherwise meal-standardized conditions. The influence of protein intake on between-day CVi is, however, unknown. The necessity for fasting has been questioned because fasting and nonfasting tHcy concentrations and reference values, as well as fasting and postprandial short-term CVi and CVg values, are similar (11)(12). We investigated whether tHcy concentrations and variations under nonfasting conditions differ from those under fasting conditions. For this we calculated tHcy biological variation from samples taken at different clock times during a single day and during 3 weeks. We studied 16 apparently healthy individuals [8 men and 8 women; median (range) age, 44 (25–58) years]. Our study design is illustrated in Fig. 1A⇓ . Six blood samples were taken from all participants on Monday of week 1. A standardized breakfast (0815 in the morning) and lunch (1215) and a dinner (1730–1800) of unrestricted composition and quantity were provided during the day. Participants documented food and beverage intake on Monday and …

Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis

BACKGROUND There is no good explanation why a proportion of patients with multiple sclerosis (MS) have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the disease course of MS. AIM To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long term dietary FA consumption, is different between patients with benign and progressive MS. METHODS The erythrocyte membrane FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS No significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found between controls and patients with the different subtypes of MS. CONCLUSION Our data suggest that factors other than dietary fatty acid consumption are responsible for the different disease courses of MS.

Controlled study on folate status following folic acid supplementation and discontinuation in women of child-bearing age.

Background To decrease the incidence of neural tube defects, active efforts are currently undertaken to promote folic acid (FA) intake among women. In 2003, the Food and Drug Administration approved the proposal of introducing an oral contraceptive (OC) and FA combination pill. It is unknown whether these pills will reduce neural tube defect incidence for couples who do not become pregnant soon after discontinuation. We studied FA kinetics up to 12 weeks discontinuation of eight weeks 500 μg/d FA in 27 healthy Dutch women of child-bearing age. Methods In this controlled study, women were assigned to an intervention group (n = 13) or a control group (n = 14). The total study duration was 20 weeks, during which the subjects had to give blood on nine occasions (week –8 [baseline], –4, 0, 1, 2, 3, 4, 8 and 12) for analyses of serum and erythrocyte folate, and plasma total homocysteine. The intervention group received 500 μg/d FA during the first eight weeks, and discontinued the intake from weeks 0 to 12. No supplements were supplied to the control group. Results Serum folate and plasma total homocysteine returned to baseline after 12 weeks of FA discontinuation, erythrocyte folate did not. Conclusion An FA/OC combination pill seems to be of value for only a minor portion of women. Active efforts to stimulate women of child-bearing age to take FA remain essential.

Maternal and fetal brain contents of docosahexaenoic acid (DHA) and arachidonic acid (AA) at various essential fatty acid (EFA), DHA and AA dietary intakes during pregnancy in mice

We investigated essential fatty acids (EFA) and long-chain polyunsaturated fatty acids (LCP) in maternal and fetal brain as a function of EFA/LCP availability to the feto-maternal unit in mice. Diets varying in parent EFA, arachidonic acid (AA), and docosahexaenoic acid (DHA) were administered from day 3 prior to conception till day 15 of pregnancy. We concentrated on DHA, AA, Mead acid, and EFA-index [(omega-3+omega-6)/(omega-7+omega-9)] in maternal erythrocytes, maternal brain, and fetal brain. It was found that erythrocyte EFA/LCP sensitively reflects declining EFA/LCP status in pregnancy, although this decline was not apparent in maternal brain. Differences in erythrocyte EFA/LCP coincided with larger differences in fetal brain EFA/LCP as compared to EFA/LCP in maternal brain. Both maternal and fetal brains were affected by short-term EFA/LCP intake, but the developing fetal brain proved most sensitive. The inverse relationship between fetal brain AA and DHA suggests the need of a maternal dietary DHA/AA balance, at least in mice.

The effects on plasma, red cell and platelet fatty acids of taking 12 g/day of ethyl-eicosapentaenoate for 16 months : dihomogammalinolenic, arachidonic and docosahexaenoic acids and relevance to Inuit metabolism

A patient with mantle cell lymphoma took 12g/day of ethyl-eicosapentaenoate for 16 months. Compared to reference values, eicosapentaenoic and docosapentaenoic acids were elevated in plasma, red cells and platelets but docosahexaenoic acid levels were in the normal range. Arachidonic acid levels were moderately reduced but dihomogammalinolenic acid levels remained in the normal range. In spite of a long chain n-3 fatty acid intake higher than in most Inuit populations, arachidonic acid levels remained considerably higher in this patient than in the Inuit. The implications for understanding of fatty acid metabolism in humans are discussed.

Inborn Errors of Metabolism That Cause Sudden Infant Death: A Systematic Review with Implications for Population Neonatal Screening Programmes

Background: Many inborn errors of metabolism (IEMs) may present as sudden infant death (SID). Nowadays, increasing numbers of patients with IEMs are identified pre-symptomatically by population neonatal bloodspot screening (NBS) programmes. However, some patients escape early detection because their symptoms and signs start before NBS test results become available, they even die even before the sample for NBS has been drawn or because there are IEMs which are not included in the NBS programmes. Objectives and Methods: This was a comprehensive systematic literature review to identify all IEMs associated with SID, including their treatability and detectability by NBS technologies. Reye syndrome (RS) was included in the search strategy because this condition can be considered a possible pre-stage of SID in a continuum of aggravating symptoms. Results: 43 IEMs were identified that were associated with SID and/or RS. Of these, (1) 26 can already present during the neonatal period, (2) treatment is available for at least 32, and (3) 26 can currently be identified by the analysis of acylcarnitines and amino acids in dried bloodspots (DBS). Conclusion: We advocate an extensive analysis of amino acids and acylcarnitines in blood/plasma/DBS and urine for all children who died suddenly and/or unexpectedly, including neonates in whom blood had not yet been drawn for the routine NBS test. The application of combined metabolite screening and DNA-sequencing techniques would facilitate fast identification and maximal diagnostic yield. This is important information for clinicians who need to maintain clinical awareness and decision-makers to improve population NBS programmes.