Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry.

OBJECTIVE: The authors examined and compared the clinical presentation of CSF positive and negative N-methyl-d-aspartate receptor (NMDAR) antibody. METHODS: The investigators performed a retrospective chart review of NMDAR-antibody-positive cases (serum or CSF) involving patients presenting to psychiatric services from 2010 to 2018 in Queensland, Australia. Presentation, progress, investigations, and efficacy of treatment are detailed. RESULTS: There were 24 serum or CSF NMDAR-antibody-positive cases and three equivocal serum results. High rates of prodromal cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity were observed in the 16 CSF NMDAR-antibody-positive case patients and two CSF NMDAR-antibody-negative case patients, all evident before neurological deterioration with seizures, movement disorder, and autonomic disturbance occurring in the weeks following admission. The majority of these patients (N=17) were treated successfully with immunomodulatory therapy. The nine remaining patients, who were CSF NMDAR antibody negative or equivocal, did not demonstrate any of these features and improved with psychiatric care alone. CONCLUSIONS: These findings suggest that traditional psychiatric care may be appropriate for patients with isolated psychiatric symptoms who have positive serum NMDAR testing when CSF is negative and there are no key clinical features such as cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity. However, if these key features are present, a trial of immunomodulatory treatment should be considered with repeated examination of CSF for neuronal antibodies.

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.

Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas L-arginine (Arg) and L-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N (G))-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S-adenosylmethionine (SAM) as the methyl donor. L-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N (G)-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N (G)-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive.

Stable isotope dilution microquantification of creatine metabolites in plasma, whole blood and dried blood spots for pharmacological studies in mouse models of creatine deficiency.

BACKGROUND: To develop an accurate stable isotope dilution assay for simultaneous quantification of creatine metabolites ornithine, arginine, creatine, creatinine, and guanidinoacetate in very small blood sample volumes to study creatine metabolism in mice. METHODS: Liquid-chromatography (C18) tandem mass spectrometry with butylation was performed in positive ionization mode. Stable isotope dilution assay with external calibration was applied to three different specimen types, plasma, whole blood and dried blood spot (DBS). RESULTS: Analytical separation, sensitivity, accuracy, and linearity of the assay were adequate. The stable isotope dilution assay in plasma revealed no significant bias to gold standard methods for the respective analytes. Compared to plasma, we observed an overestimate of creatine and creatinine (2- to 5-fold and 1.2- to 2-fold, respectively) in whole-blood and DBS, and an underestimate of arginine (2.5-fold) in DBS. Validation of the assay in mouse models of creatine deficiency revealed plasma creatine metabolite pattern in good accordance with those observed in human GAMT and AGAT deficiency. Single dose intraperitoneal application of ornithine in wild-type mice lead to fast ornithine uptake (Tmax ≤ 10 min) and elimination (T1/2=24 min), and a decline of guanidinoacetate. CONCLUSION: The assay is fast and reliable to study creatine metabolism and pharmacokinetics in mouse models of creatine deficiency.

[Mismatch negativity and its hemodynamic equivalent (based on fMRI) in research of speech perception in healthy and in speech disorders].

The review is devoted to the use of electrophysiological index of auditory discrimination, known as "mismatch negativity" (MMN), and its hemodynamic equivalent obtained by functional magnetic resonamce imaging (fMRI) to study speech perception in normal and pathological conditions. Most attention is paid to works with using MMN as a neurophysiological index of the phonemic hearing impairment in patients with sensory aphasia. The MMN applicability for examination of speech compensation degree is substantiated. Also the perspectives of simultaneous EEG-fMRI registration in exploring speech pathologe are considered.

Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine.

Low plasma homoarginine has emerged as a risk marker for cardiovascular disease. We exploited cells of a patient with a rare inborn error of metabolism to explore potential pathways of homoarginine synthesis, using stable isotopes and mass spectrometry. Control lymphoblasts, as opposed to lymphoblasts from an arginine:glycine amidinotransferase (AGAT)-deficient patient, were able to synthesize homoarginine from arginine and lysine. In contrast, in a patient with a deficiency of the urea cycle enzyme argininosuccinate synthase, plasma homoarginine was not decreased. We conclude that promiscuous activity of AGAT, a key enzyme in creatine synthesis, plays a pivotal role in homoarginine synthesis.

Speech impairment in primary hypothyroidism.

OBJECTIVE: Thyroid hormone deficiency may affect human speech and voice. The aim of this study was to evaluate speech variables in patients with hypothyroidism. DESIGN: A case control study. PATIENTS: One hundred and twenty patients, 106 women and 14 men with symptoms and signs of thyroid failure; the diagnosis was confirmed by serum T4<4.5 µg/dl and serum TSH>10 mU/l. Eighty-eight normal subjects, 78 women and 10 men, age-, sex-, and smoking status- matched, served as controls. MEASUREMENTS: All symptoms and signs of hypothyroidism were recorded. Serum T4, T3, and TSH concentrations were measured. Speech parameters were analyzed by the Visipitch III system model 3900 and multidimensional voice program software and compared to a group of normal subjects with no thyroid disease. RESULTS: Mean age was 35.9±11.4 yr. Dryness in larynx and pharynx, dyspnea, and sensation of lump in the throat were reported by 53.49 and 43% of patients, respectively. Fundamental frequency, voice turbulence index, and soft phonation index were significantly different from control values. There was positive correlation between TSH concentration and variation in fundamental frequency and prevalence of voice disorders (37.2±31.2 vs 23.9±25.8 mU/l, p<0.003). CONCLUSION: Frequent speech disturbances occur in patients with primary hypothyroidism.

Aluminio en pacientes con terapia de reemplazo renal crónico con hemodiálisis en dos unidades renales en Bogotá / Aluminium in chronic renal replacement therapy patients undergoing haemodialysis in two renal units in Bogotá

Objetivo Determinar las concentraciones de aluminio en suero de pacientes con terapia de reemplazo renal crónico con hemodiálisis y las concentraciones en agua de redes de distribución y diálisis en dos unidades renales en Bogotá. Material y Métodos Estudio descriptivo en 63 pacientes en hemodiálisis y 20 individuos sanos. Las concentraciones de aluminio se determinaron por espectrofotometría de absorción atómica horno de grafito con corrección de lámpara de deuterio. Resultados El promedio de las concentraciones de aluminio en suero de los pacientes fue de 26,5 µg/L (11,2 a 49,2 µg/L, DE=8,03), en individuos sanos de 8,05 µg/L (menor al Límite de Detección a 17,2 µg/L, DE=4,31), en agua de diálisis fue menor a 2 µg/L y en agua de las redes de distribución menor a 200 µg/L. Conclusiones Las concentraciones de aluminio en el agua de la red de distribución y diálisis estudiadas se encontraron por debajo de los valores establecidos internacionalmente indicando un adecuado tratamiento de las mismas. Igualmente las concentraciones de aluminio pre-HD y post-HD observadas en los pacientes se encontraron por debajo de las reportadas en la literatura. El consumo de hidróxido de aluminio aumenta significativamente la concentración de aluminio en suero. Variables como edad, género, estado civil y situación laboral no son factores de riesgo que alteren significativamente las concentraciones de aluminio en suero.

Objective Determining aluminium concentrations in the serum of patients undergoing chronic renal replacement therapy with haemodialysis and concentration in distribution network water and dialysis in two renal units in Bogotá. Material and Methods This was a descriptive study of 63 haemodialysed patients and 20 healthy subjects. Aluminium concentration was determined in water and serum using graphite furnace atomic absorption spectrometry with deuterium lamp background corrector. Results Average aluminium concentration was 26.5 µg/L in patients (ranging from 11.2 to 49.2 µg/L; 8.03 standard deviation) and 8.05 µg/L in healthy individuals (ranging from undetectable to 17.2 µg/L; 4.31 standard deviation). Aluminium concentration in dialysis water and distribution network water was below 2 µg/L and 200 µg/L, respectively. Conclusions Aluminium concentration in water and serum in this study was below international standard values, thereby indicating appropriate treatment. Additionally, aluminium concentration in pre-HD and post-HD sera was below that reported previously. Aluminium hydroxide uptake increases aluminium concentration in serum. Personal situation regarding age, gender, civil and work status were not risk factors determining aluminium concentrations in serum.

Endogenous oestrogens predict 4-year decline in verbal fluency in postmenopausal women: the Rancho Bernardo Study.

OBJECTIVE: Despite overwhelming biological plausibility, evidence for a protective effect of oestrogen on cognitive function in postmenopausal women is inconsistent. This study examines the association between endogenous oestrogen levels and subsequent 4-year decline in cognitive function test performance in community-dwelling older women. DESIGN: Longitudinal cohort study. PARTICIPANTS: Three hundred and forty-three postmenopausal women (median age 70 years). MEASUREMENTS: Between 1984 and 1987, serum for measurement of sex hormones was obtained along with relevant covariates. Cognitive function was assessed in 1988-1991 and again in 1992-1996 using the Category Fluency test, the Mini-Mental Status Exam (MMSE) and Trail Making Test B (Trails B). RESULTS: Women in the highest tertile of oestrone and bioavailable oestradiol had respectively 1.75 (95% CI 1.02, 3.07) and 1.79 (95% CI 1.04, 3.10) higher odds of 4 year decline in Category Fluency, a test of frontal lobe function, compared to those in the lowest tertile, independent of age and education. The 20% of women with highest tertile levels of both oestrone and bioavailable oestradiol had a twofold higher odds of verbal fluency loss (OR = 2.17; 95% CI 1.21, 3.89). Adjustment for testosterone levels or for obesity-related factors associated with high endogenous oestrogens (higher body mass index, waist girth, and triglycerides and lower high-density lipoprotein cholesterol) did not alter results. Neither oestrogen was associated with change in MMSE or Trails B scores. CONCLUSIONS: Higher endogenous oestrogen levels were associated with a greater decline in verbal fluency in postmenopausal women. This association was not explained by elevated androgens or by obesity or obesity-related factors.

[Aluminium in chronic renal replacement therapy patients undergoing haemodialysis in two renal units in Bogotá]. / Aluminio en pacientes con terapia de reemplazo renal crónico con hemodiálisis en dos unidades renales en Bogotá.

OBJECTIVE: Determining aluminium concentrations in the serum of patients undergoing chronic renal replacement therapy with haemodialysis and concentration in distribution network water and dialysis in two renal units in Bogotá. MATERIAL AND METHODS: This was a descriptive study of 63 haemodialysed patients and 20 healthy subjects. Aluminium concentration was determined in water and serum using graphite furnace atomic absorption spectrometry with deuterium lamp background corrector. RESULTS: Average aluminium concentration was 26.5 µg/L in patients (ranging from 11.2 to 49.2 µg/L; 8.03 standard deviation) and 8.05 µg/L in healthy individuals (ranging from undetectable to 17.2 µg/L; 4.31 standard deviation). Aluminium concentration in dialysis water and distribution network water was below 2 µg/L and 200 µg/L, respectively. CONCLUSIONS: Aluminium concentration in water and serum in this study was below international standard values, thereby indicating appropriate treatment. Additionally, aluminium concentration in pre-HD and post-HD sera was below that reported previously. Aluminium hydroxide uptake increases aluminium concentration in serum. Personal situation regarding age, gender, civil and work status were not risk factors determining aluminium concentrations in serum.

Hyperserotonemia in adults with autistic disorder.

Hyperserotonemia is the most consistent serotonin-related finding in autism. The basis of this phenomenon, and its relationship to the central serotonergic dysfunction remains unclear. Platelet serotonin level (PSL) in 53 autistic adults and 45 healthy controls was measured. Mean PSL in autistic group (75.7 +/- 37.4 ng/microL) was significantly higher than the control sample (59.2 +/- 16.2 ng/microL) due to a presence of hyperserotonemic subjects which comprised 32% of the patients. PSL of autistic subjects did not correlate with the severity of symptoms, as measured by total CARS score, or the degree of mental retardation. However, significant negative relationship was observed between PSL and speech development, indicating the relationship between the peripheral 5HT concentrations and verbal abilities in autistic subjects.

Relationship between oral motor dysfunction and oral bacteria in bedridden elderly.

OBJECTIVE: The purpose of this study was to analyze the relationship between oral bacterial colonization and oral motor dysfunction. STUDY DESIGN: Oral motor dysfunction (swallowing and speech disorders) and detection of oral bacterial species from dental plaque in 55 elderly persons who had remained hospitalized for more than 3 months were investigated and statistically analyzed. RESULTS: The detection rates of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Streptococcus agalactiae, and Stenotrophomonas maltophilia were significantly higher in subjects with than in those without a swallowing disorder. A similar result was found with regard to the presence of a speech disorder. About half of subjects who had oral motor dysfunction and hypoalbuminemia had colonization by MRSA and/or Pseudomonas aeruginosa. CONCLUSION: These results suggest that the combination of oral motor dysfunction and hypoalbminemia elevated the risk of opportunistic microorganisms colonization in the oral cavity of elderly patients hospitalized over the long term.