[Homocysteinemia and thrombophilic factors in unexplained decompression sickness]. / Homocystéinémie et facteurs de thrombophilie dans des accidents de décompression immérités chez des plongeurs.

INTRODUCTION: Decompression sickness with cerebral ischemic lesions occurs even in divers who have not committed any technical error. This study sought to determine whether an acquired or inborn thrombophilic factor might be involved. METHODS: 44 divers with ischemic medullar lesions (36 men, 8 women, mean age 39.9+/-4.7 yr) were compared with 44 controls (34 men, 10 women, mean age 38.2+/-5.1 yr). Coagulation screening included proteins S, C, and thrombin III and Factor VIII assays and circulating antibodies, Factor V Leiden, and mutation G20210A in Factor II gene research. Total plasma homocysteine (Hcy), an atherosclerosis factor (assayed by FPIA), folate and vitamin B12, (by microbiology), the cofactors of its metabolism, were assayed, and subjects were genotyped for mutation C677T on the MTHFR gene. RESULTS: Coagulation screening--protein C, protein S, or antithrombin III deficit or mutation G20210A--was negative in all divers. 3/44 divers were heterozygous for Factor V Leiden, 1/44 had IgG antiphospholipid antibodies (9p.cent). While not found in controls, these percentages were not greater than those reported in the general population. 3/44 divers had elevated Factor VIII levels, but repeat assays on Day 2 were much lower. 11/44 divers had a moderate increase in Hcy value (20p.cent): in 7 divers, Hcy values were>15 micromol/L, and in 4 others>12, vs. 2.3p.cent of the controls; 2/11 had normal vitamin levels and 11 divers had folate or vitamin B12 deficiency or both, vs 2.3p.cent controls with a vitamin B12 deficit (percentage significantly different). 7/26 divers were homozygous for the C677T mutation, i.e. 27p.cent vs 12p.cent of 98 healthy controls (laboratory technicians). CONCLUSIONS: A high percentage of unexplained diving accident victims had moderate HHC, a folate or vitamin B12 deficiency or both, that are easy to detect, plus a genetic predisposition to HHC or to coagulation abnormality. Easy-to-perform homocysteine, vitamin B12, and folate assays might prove helpful for primary prevention of diving accidents.

Whole blood serotonin content, tryptophan concentrations, and impulsivity in anorexia nervosa.

BACKGROUND: We hypothesized that anorectics with or without bulimic features would differ on impulsivity and indices of central serotoninergic function (high impulsivity being correlated with reduced serotoninergic function). METHODS: For all patients impulsivity rating scales and questionnaires detailing severity of eating disorder were assessed, and whole blood serotonin concentration (5-HT), free and total tryptophan (TT) concentrations, and large neutral amino acids (LNAA) were assayed. RESULTS: Nineteen patients with anorexia nervosa were included, 10 presented associated bulimic features and nine did not. Twelve healthy matched controls were also included. Our hypothesis was not verified. However, tryptophan concentration and the ratio of tryptophan concentration to LNAA allow us to separate controls from anorectics, whereas 5-HT concentration does not. Two significant and positive correlations were found: between impulsivity and anxiety in the total anorectic population, and between anxiety and serotonin in the impulsive group. CONCLUSIONS: All measured peripheral biologic indices except 5-HT concentration may be of interest in this pathology. Impulsivity and anxiety seem to be two personality components involved in anorexia nervosa. This study lead us to the necessity of redefining impulsivity in anorexia nervosa.

Diurnal variation in total plasma tryptophan in controls and in depression.

Circadian rhythms of total tryptophan were investigated by assays of hourly blood samples over 25 h. The study population consisted of four endogenously depressed patients investigated in the absence of any treatment and six healthy controls. The abnormalities detected by statistical analyses in untreated depression consisted mainly of amplitude reduction; the phase positions of the depressed patients were similar to those of the controls.

[Clinical relevance of homocysteine monitoring in the diabetic patient]. / Faut-il doser l'homocystéine chez le patient diabétique?

Accelerated atherosclerosis is common in diabetes mellitus, although its extent is not always related to its strong association with classical cardiovascular risk factors. Diabetic patients, especially with type 2 diabetes, are prone to cardiovascular disease which is the leading cause of death in this population. Recent clinical studies among general population have shown that an even mild increase of homocysteinemia play an important role in the progression of atherosclerosis, either in coronary or peripheral arteries. An increasing amount of in vitro data is providing evidence that excess of homocysteine has a toxic effect on the arterial wall. This aminoacid thus appears to be not only a risk marker but also an emerging cardiovascular risk factor. The measurement of plasma homocysteine contributes to the identification, among the diabetic population, of patients at high cardio-vascular risk, with the aim of improving their global management. Moreover the addition of group B vitamins provides an easy and low-cost treatment to lower hyperhomocysteinemia.

Circadian variation in total plasma tryptophan. Antidepressant treatment: drugs and phase advance.

The authors investigated hourly total plasma tryptophan concentrations over a 24 hour period in 3 patients with bipolar depression during 2 types of treatment: a phase advance process and conventional antidepressant therapy. Both treatment modalities increased the 24 hour mean tryptophan levels and the amplitude of circadian tryptophan concentrations. By contrast, in a previous study, moderately decreased tryptophan levels and a blunted amplitude in the circadian rhythm were observed in these same patients in a depressive phase.

5-Methoxypsoralen: effect on the noradrenaline circadian rhythm of sleep-deprived subjects.

5-methoxypsoralen (5-MOP), a serotonin analogue, stimulates the secretion of melatonin, which plays an important role in circadian rhythm regulation. Melatonin production is essentially controlled by noradrenaline (NA). To investigate the effect of 5-MOP on the 24 hr NA rhythm, hourly plasma NA concentrations measured over 24 hr in 7 healthy young subjects who took 40 mg 5-MOP orally at 21:00 hr the evening before were compared with values obtained in drug-free subjects. All subjects were sleep-deprived and under conditions in which sympathetic nervous system activation was repeated every hour over 24 hr. In both series of patients, a significant difference was observed between mean morning values and mean night values, reflecting persistence of a circadian rhythm. In subjects given 5-MOP, a significant difference was also observed between mean afternoon values and mean night values. However, MANOVA analysis failed to find any difference between the two series of subjects. Acute administration of 5-MOP thus had no significant effect on the NA circadian rhythm under our study conditions.

Tryptophanemia and tyrosinemia in adolescents with impulsive behavior.

Tryptophan (TRP) and tyrosine (TYR), respectively the circulating precursors of the central serotonergic (5-HT) and catecholamine systems, were measured in eight adolescents with impulsive behavior regardless of the exact type of disorder. The 6 week study period included weekly blood sampling and clinical evaluation. The ratios of TRP and TYR to large neutral amino acids (LNAA), which indicate the availability for the synthesis of neurotransmitters, were calculated. Comparison of results with eight hospitalized controls of the same age (12.5 to 18 years) revealed lower total TRP levels in four adolescent patients, a lower TRP/LNAA ratio in three adolescents, and a lower free TRP concentration in six adolescents with discretely enhanced albuminemia. A slight increase in TYR and the TYR/LNAA ratio was noted in nearly all of the adolescent patients. Despite the heterogeneity of individual biological results, the impulsive behavior subjects in this study seemed to present abnormalities in neurotransmitter precursors.

Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality.

Circadian rhythms of body temperature, plasma cortisol, norepinephrine (NE), thyroid stimulating hormone (TSH), and melatonin were compared in 16 endogenously depressed, 15 recovered (after 3 weeks of anti-depressant treatment), and 16 normal subjects. The depressed patients showed clear circadian rhythm abnormalities, consisting mainly in amplitude reduction. This amplitude reduction was significantly correlated with the patients' Hamilton depression scores. Normal circadian profiles were restored after recovery when amplitude, in particular, was increased. Features of the circadian rhythms observed in remission may be associated with antidepressant drug effects, whereas those observed in depression resemble the circadian rhythms observed in normal subjects living under conditions of temporal isolation and those of blind subjects. Our findings suggest that depression may be related both to a weakening of the coupling processes between internal pacemakers and to an abnormal sensitivity to environmental information.

Circadian rhythm in plasma noradrenaline of healthy sleep-deprived subjects.

Under normal sleep-wake conditions, noradrenaline (NA) secretions in supine subjects exhibit a weak circadian variation with a peak that occurs around noon; the sleep span is characterized by reduced NA secretion. Some investigators have reported that the circadian NA rhythm is completely obliterated during sleep deprivation. In our laboratory, plasma NA was assayed every hour for 24 h in nine healthy men 20-23 years of age. All men were deprived of sleep and were required to eat and walk around every hour to prevent sleep. However, subjects remained supine for 20 min before blood samples were collected to eliminate the effect of activity. Persistence of a slight decrease in the night concentration in several subjects, despite sleep deprivation, suggests that NA secretion may be influenced by a biological clock whose activity becomes visible when the influence of posture is removed.

Changes in lymphocyte beta-adrenoceptor density after dilevalol oral treatment.

Dilevalol (R,R'-isomer of labetalol) is an antihypertensive agent combining non-specific beta blockade with peripheral vasodilatation due to beta 2-receptor agonism. The aim of this study was to determine the effects of chronic dilevalol administration on lymphocyte beta 2-adrenoceptor density. The investigation was conducted as a double-blind, placebo-controlled comparison. Ten days of chronic dilevalol (400 mg) or placebo treatment was administered to 12 healthy normotensive volunteers. Clinical and biochemical parameters: heart rate (HR) systolic and diastolic blood pressure (SBP, DBP), electrocardiogram, norepinephrine (NE), epinephrine (E), MHPG (3-methoxy-4-hydroxyphenylethylene glycol; one of the major brain metabolites of NE) were analysed on the first day (D1) before (H0) and 3 h after oral treatment (H3) and on the tenth day (D10). Clinical results showed no significant changes in HR, DBP, SBP in the two groups (placebo, n = 6; dilevalol, n = 6). NE increased 3 h after the first oral dilevalol intake (p less than 0.05). This increase is greater than that due to the circadian variation observed in the placebo group. Acute dilevalol treatment seems to increase the plasma circulating NE level, which returns to normal values after 10 days of chronic treatment. Binding assays were performed before and after 10 days of treatment. In the placebo group, no change in beta-adrenoceptor density was observed (36.6 +/- 8.3 versus 38.3 +/- 9.4 femtomol/mg of protein). Lymphocyte beta-adrenoceptor density (Bmax) significantly decreased after 10 days of dilevalol treatment without any changes in affinity (KD). Results were 40.3 +/- 11.6 (D1) and 30 +/- 7.6 (D10) (p less than 0.05). It was concluded that dilevalol down-regulated lymphocyte beta 2-adrenoceptor density, suggesting that beta 2 agonism of dilevalol is predominant.

Effects of strength exercise and training on the natural killer cell counts in elderly humans.

BACKGROUND: To investigate the effects of strength exercise and training on the natural killer cell counts in elderly humans. METHODS: The study examined strength exercise-induced changes in the number of NK cells and changes in stress hormones in 16 sedentary elderly subjects before and after a 8-week strength training intervention. Blood samples were obtained before, immediately and 6 hours after a standardized strength test. Blood samples were also obtained from ten sedentary young subjects, under the same conditions and from ten resting elderly subjects serving as time controls. RESULTS: Prior to training, older adults immediately decreased (from 165.4+/-19.5 microL to 110.6+/-14.3 microL; mean+/-SEM) their NK cell count in response to the standardized strength test, whereas young controls increased their count (from 157.6+/-28.8 microL(-1) to 241.4+/-39.8 microL(-1)). After strength training, the same old subjects slightly increased (from 159+/-19.8 microL(-1) to 166.6+/-19.7 microL(-1)) their NK cell counts in response to the standardized strength test. In elderly subjects, no increase in stress hormone was observed following the strength test either before or after the strength training programme. CONCLUSIONS: The results suggest that in sedentary older adults, unlike young subjects, strength exercises can induce a transient decrease in NK cell count which can be cancelled by a short-term strength conditioning. Therefore, caution should be taken regarding immunocompetence of older adults when initiating a rehabilitation programme based on strength.

[Acute polyradiculoneuritis and dysautonomia: contribution of assaying catecholamines and their methoxylated metabolites]. / Polyradiculonévrites aiguës et dysautonomie: pertinence du dosage des catécholamines et des dérivés méthoxylés.

Guillain-Barré syndrome is an acute demyelinating polyradiculoneuritis usually evolving with rapid, functional recovery. In severely paralysed patients, cranial nerve palsy and autonomic nervous system dysfunctions are common. Lesions of the spinal roots predominate but segmentary demyelination of peripheral nervous system reflects various clinical subtypes. Twelve patients (42,8 p. cent) had clinical dysautonomia. Ten had an increase of urinary methoxylated metabolites. Patients exempt of dysautonomia had normal biological parameters. The elevated level of urinary methoxylated metabolites is statistically correlated to clinical dysautonomia and can be used as a biological marker to monitoring demyelinating polyradiculoneuritis.

[Neural tube defects and vitamin B12: a report of three cases]. / Anomalies du tube neural et vitamine B12: à propos de trois cas.

Periconceptional folic acid supplementation reduces the frequency of embryological neural tube defects (NTD). This fact led the USA to fortify grain products with folic acid (140 microg/100 g) starting in January 1998, with a resultant decrease in the incidence of NTD. Folate deficiency is thus confirmed to be a risk factor for NTD. However, in a prospective study, we investigated three women who conceived a fetus with NTD; no folate deficiency was found in these women but all three had decreased vitamin B12 levels (cobalamin), which can be an other risk factor. Samples were obtained from two women in Algeria, 2 days after interruption of pregnancy, and from a vegetarian woman, in France, one month after interruption of pregnancy. Red cell folate and plasma folate, vitamin B12, B6 and homocysteine were assayed and the mutations C677T (in metylenetetrahydrofolate reductase gene), A2756G (in methionine synthase gene) and A66G (in methionine synthase reductase gene) were sought. Elevated plasma folate levels were found in both Algerian women. Vitamin B 12 levels in all three women were decreased or in the lowest quartile of normal values. One woman presented simultaneously a vitamin B 12 deficiency, and heterozygous mutations in the three genes. The second woman presented a A66G homozygous mutation and the third heterozygous C677T and A66G mutations. Acquired and inborn factors are intricated in some cases of pregnancies with NTD and B 12 deficiency can be responsible for intracellular folate cycle failure. It would therefore be advisable to consider fortifying grain products with both folic acid and vitamin B12.

[Plasma homocysteine measurement: a study of pre-analytical variation factors for conditions for total plasma homocysteine concentration]. / Dosage de l'homocystéine plasmatique: étude des facteurs de variation préanalytiques sur la concentration en homocystéine plasmatique totale.

An increase in homocysteine, a sulphur amino acid, is nowdays considered as a risk factor for cardiovascular diseases, and is independent of other risk factors. Reference range for total plasma homocysteine level in adults is usually 5-15 mmol/l. Hyperhomocysteinemia is defined as a fasting total plasma homocysteine level > 15 mmol/l. There may be also graded increased risks for subjects with homocysteinemia from 10 to 15 mmol/l. However, no threshold has been defined, partly because of the lack of standardization in pre-analytical and analytical steps. The aim of the present work was to evaluate three pre-analytical parameters on plasma homocysteine levels: i) the influence of three anticoagulants (EDTA, sodium citrate and lithium heparin); ii) the delay period of blood sample on ice before centrifugation; and iii) the advantages of strong acidic citrate at room temperature. The mean concentrations of total plasma homocysteine were different in function of the anticoagulant. These differences (EDTA minus lithium heparin or EDTA minus sodium citrate) were less than 10% however the used methods and could explain the good correlation between the results. However we recommend to keep the anticoagulant constant in the same study. When EDTA blood samples were immediately put on crushed ice, the maximum delay period before centrifugation could reach 4 hours. If ice is unavailable, strong acidic citrate at room temperature is a good alternative until for 4 hours.

[Comparison of plasma total homocysteine determinations in 9 French hospital laboratories by using 6 different methods]. / Comparaison du dosage de l'homocystéine plasmatique totale dans neuf laboratoires par six techniques différentes.

A lot of methods are now available for total plasma homocysteine (tHcy) determination. Commercial kits using immunoassay, easier to use, begin to supplant in-house laboratory methods. Our aim is to evaluate the interchangeability of tHcy measurements in 9 French hospital laboratories. Six different method types were used: 2 gas chromatography-mass spectrometry (GC-MS), 2 HPLC with fluorescence detection subdivided in one in-house method and one commercial kit (Bio-Rad ), 3 fluorescence polarization immunoassays (FPIA), 1 enzyme immunoassay, 1 amino acid analyser, 1 capillary electrophoresis coupled with laser-induced fluorescence detection (EC-LIF). Each laboratory analysed 41 patient's plasma samples in which 8 samples contained added homocystine. Results were analysed for imprecision, recovery, and methodological differences. The mean among-laboratory imprecision (CV) ranged from 12.5 to 18% in function of plasma sample type and was identical to the mean among-method variation. In terms of recovery, we obtained underestimated results with immunoassays. The bias relative to the GC-MS method was less than 12.5% except for two laboratories, one using FPIA assay and the other EC-LIF. In conclusion, the interchangeability of tHcy results between laboratories is not satisfactory and does not allow us to evaluate cardiovascular risk linked to moderate increases of tHcy.

[Biochemical diagnosis of pheochromocytoma and neuroblastomas]. / Diagnostic biochinique du phéochromocytome et du neuroblastome.

Pheochromocytoma and neuroblastoma are distinct tumours, but their biological diagnosis is based on secretion increase of one or several catecholamines. Assays have to be very sensible and specific for an early diagnosis. 24 hours urinary catecholamines and metabolites are currently measured, but technical improvements permit plasma metanephrine assay, an excellent indicator of pheochromocytoma. HPLC coupled to electrochemical detection represents the most efficient methodology. After a review of urinary and plasma assay methods, the authors show usual values of catecholamines, metanephrines, HVA and VMA, according to ages, and give examples of results encountered in classical or not tumours and in falsely positive cases. Urinary metanephrine assay is the most sensible and specific in biological diagnosis of pheochromocytoma, while catecholamines and VMA assays lack of sensibility. Results have to be given by 24 hours and by creatinine ratio. Metanephrine assay can be performed also in plasma and exhibits the same interest. However, in urine as in plasma, in case of renal failure, results cannot be interpreted. Neuroblastoma biological diagnosis is based classically on HVA, VMA, and dopamine assays, nowadays only in 24 hours urine (or in urinary micturition for screening), and results are also expressed as creatinine ratio. But even if several assays are advisable, 5% of the neuroblastoma cases do not produce increased catecholamine values. In some cases, metanephrine assay could be of interest. After the age of 12 months, clinical expression of neuroblastoma is dramatic in 70% of cases. So, a biological screening has been experimented in several countries including France. A French translation of the consensus conference report (1998) is appended, which shows the complexity of neuroblastoma screening. Now, there is no evidence that early tumour detection by screening lessens the mortality rate, but a weak benefit is not excluded.

[Principle methods of determining plasma 3-methoxy-4-hydroxyphenyl glycol]. / Principales méthodes de dosage du 3-méthoxy-4-hydroxyphényl glycol plasmatique.

The dosage of plasma 3-methoxy-4-hydroxyphényl glycol (MHPG) presents a great interest, specially in psychiatry. Several methods are described: gas chromatography, with or without mass spectrometry, high performance liquid chromatography with some internal standard problems and with different modes of extractions and radioimmunoassay. Every method presents advantages but also inconveniences which are discussed.

[Plasma tryptophan in a protein controlled diet in depressed patients]. / Tryptophane plasmatique à apport protéique contrôlé chez des déprimés.

Cerebral serotonin is synthetized from its blood precursor: tryptophan (TRP), an essential amino acid (6). TRP has been extensively studied since serotonine has been reported to be involved in the pathogenesis of depression (9). In one hand, brain serotonin content depends on regulation by plasma large neutral amino acids (LNAA): leucine, isoleucine, valine, tyrosine and phenylalanine that compete with TRP to cross over the blood brain barrier (7, 13). In the other hand TRP is largely linked with albumin. So, we have studied plasma total TRP, free TRP and the ratio TRP on LNAA as potential cerebral serotonin index. The aim of this study is to observe the blood variations of the biological parameters in fasting and postprandial conditions in 8 depressed women, aged from 57 to 78 years, on a short protein controlled diet: 4 women had TRP poor then rich diet and the others 4 rich then poor. Alimentary proteins modulated diets and each patient was his own control: the results under modulated diet were compared with those under normal diet at the same time. More over, 2 psychotic patients aged 58 and 70 years have been studied at the same time, in each group. Biological datas were compared with clinical evolution.

[Circadian rhythm of plasma norepinephrine in depressive disorders. Preliminary study]. / Rythme circadien de la noradrénaline plasmatique dans les désordres dépressifs. Etude préliminaire.

The biological desynchronisation hypothesis of (endogenous) depressive disorders arises from the disturbances in the circadian rhythmicity of several biological functions in depressive illness and clinical improvement during various sleep deprivation processes. Furthermore, supportive evidence exists to postulate a central noradrenergic dysfunction, at least in a sub group of depressive disorders. We studied the 24 h kinetics of plasma norepinephrine in patients suffering from Affective Disorders-Major Depressive Episode according to DSM III criteria. Blood samples were drawn hourly from an indwelling venous catheter in supine subjects. Plasma NE was measured by HPLC with electrochemical detection. 5 patients (age: 35-63) were studied in base line drug free depressive state and compared with 5 control subjects (age: 44-53), then, in 4 patients, on the 8th and 21st days under antidepressant treatment. Control subjects exhibited a circadian rhythm of TP but a weak amplitude and low values during sleep, as previously described. Depressed patients did not display any rhythmicity because of a reduced amplitude and high plasma levels during sleep. Antidepressants did not restore the rhythm. Our results suggest a rhythmic instability involving a circadian lability linked to an ultradian release during sleep. This NA disinhibition could participate in the depressive desynchronisation and the potential relationships with sleep disorders must be discussed.

[Nocturnal-diurnal changes of norepinephrine blood levels in patients with chronic cardiac insufficiency. Practical values]. / Variations nycthémérales du taux de la noradrénaline dans le sang des insuffisants cardiaques chroniques. Intérêts pratiques.

The purpose of this study was to investigate circadian changes in noradrenaline (norepinephrine) levels in patients presenting with congestive heart failure. Eighteen patients were investigated with a group mean age of 66 years, 12 in NYHA class III and 6 in class IV. The cause of the heart failure was ischemia in 7 cases, valvular in 1 case and idiopathic in the other 10 cases. The mean follow-up time of the disease was 3.9 years. Six healthy volunteers were investigated following the same protocol. Blood samples were taken while the patient was lying down over a period of 24 hours, after installing a peripheral venous catheter. The assay was carried out by means of high performance liquid chromatography with electrochemical detection. In the controls, the mean noradrenaline level (norepinephrine) was 220 +/- 62 pg/ml, with daytime peaks. The heart failure patients showed a high mean level (230 +/- 404 pg/ml), with less daytime variability than the controls (92% vs 127%; p < 0.05). The 8 a.m. value was reproducible, and there was close correlation between this value and the mean value for the 24 hours (p < 0.001). Thus, the morning sample provides a good estimation of the levels over the 24 hours.