A comparative and longitudinal study on endocrine changes related to ovarian function in patients with anorexia nervosa.

Screening of androgens and estrogens in blood and a GnRH test were performed in 20 female patients with anorexia nervosa and in 10 lean and 10 normal weight healthy control subjects. Both control groups had regular ovulatory menstrual cycles. The investigation was performed in the mid-follicular phase. Several variables showed significant differences between the groups; the levels of PRL, estrone, estradiol, progesterone, testosterone, androstenedione, and LH were lowest in the patients with anorexia nervosa. The lean control group showed intermediate values for progesterone, androstenedione, and, to a smaller extent, testosterone. The FSH response to GnRH was significantly higher in the patient group, corresponding to the pattern of late prepubertal girls. Ten patients were seen in a follow-up study. Five had resumption of the menstrual cycle, and the others still had amenorrhea. The two subgroups did not differ in either weight gain or the basal hormonal variables investigated. After weight gain an increased LH response to GnRH was observed in both subgroups. Patients who had resumption of the menstrual cycle showed a higher response of LH to GnRH, both before and after weight gain. The mean increase in LH after GnRH administration was significantly different between the two subgroups. The results suggest that the GnRH test may be useful to assess the stage of the disease and to predict the outcome, especially with regard to restoration of the menstrual cycle.

Neuroexcitatory plasma amino acids are elevated in migraine.

To investigate the role of glutamic (Glu) and aspartic acid (Asp) in migraine, we measured the plasma amino acids in migraine patients with and without aura, between and during attacks, and compared the profiles with the plasma amino acid profiles of tension headache patients and healthy controls. Between attacks, migraineurs (notably with aura) had substantially higher plasma Glu and Asp levels than did controls and tension headache patients. In addition, patients with migraine without aura showed low plasma histidine levels. During migraine attacks, Glu (and to a lesser extent Asp) levels were even further increased. The results suggest a defective cellular reuptake mechanism for Glu and Asp in migraineurs, and we hypothesize a similar defect at the neuronal/glial cell level, predisposing the brain of migraineurs to develop spreading depression.

Serotonin metabolism in migraine.

To investigate systemic serotonin (5-HT) metabolism in migraine, we determined platelet and platelet-free plasma concentrations of 5-HT, its precursors tryptophan and 5-hydroxytryptophan, and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA), as well as the activities of the platelet enzymes monoamine oxidase and phenolsulfotransferase in classic and common migraineurs. Between attacks, migraineurs had lower plasma 5-HT and higher 5-HIAA levels than did healthy controls and patients with tension headache. During migraine attacks, plasma 5-HT levels were substantially higher than during attack-free periods, while 5-HIAA concentrations and platelet enzyme activities were lower. Platelet 5-HT was reduced only during common, but not classic, migraine attacks. We hypothesize that systemic 5-HT metabolism is enhanced in migraineurs during headache-free periods and transiently decreases during attacks, presumably due to a fall in enzymatic degradation. Furthermore, platelet behavior differs during migraine attacks with and without aura, and release of platelet 5-HT cannot (exclusively) be held accountable for the rise of plasma 5-HT during migraine attacks.

Platelet preservation. II. The response of human platelet suspensions to hypotonic stress.

1. Platelet suspensions were exposed to hypotonic stress. Several parameters of the changes in light absorbance were investigated i.a. the initial decrease in absorbance (A min), the maximal rate of the recovery process (V max), and the value of the absorbance two hours after mixing the platelet suspension with the hypotonic solution. 2. The ratio V max/A min appeared to be independent of both platelet concentration and, within a specific range, decrease in osmolarity. 3. Cryoprotectants appeared to disturb the response to hypotonic stress. 4. Cryopreservation caused a decrease in the light absorbance of the platelet suspension, of A min, and of the recovery process.

Platelet preservation. III. The influence of dimethylsulfoxide and cooling conditions on serotonin uptake velocity and response to hypotonic stress of human platelets.

1. Serotonin uptake velocity of human platelets was found to be reversibly inhibited by the presence of dimethylsfulfoxide (DMSO). 2. Incubation of platelet concentrates in the presence of DMSO for 90 minutes at room temperature decreased serotonin uptake velocity and response to hypotonic stress. 3. The serotonin uptake velocity was not substantially influenced by the temperature of incubation with DMSO. 4. The best recovery of serotonin uptake velocity after cryopreservation in the presence of DMSO was observed when DMSO was added quickly before cooling and removed quickly after thawing. 5. No significant differences were observed in serotonin uptake velocity and response to hypotonic stress cryopreservation in the presence of DMSO when cooling rates were varied from 2 to 10 degrees C/min.

Serum uric acid correlates in elderly men and women with special reference to body composition and dietary intake (Dutch Nutrition Surveillance System).

In 460 apparently healthy Dutch elderly, aged 65-79 years, serum uric acid correlates were studied by linear regression analyses, for men and women separately. Diuretic therapy, total serum cholesterol (women only) and creatinine clearance (in bivariate analysis only) were significantly associated with serum uric acid level. Positive associations of serum uric acid with body weight, body mass index, body fatness (men) and lean body mass (men) were observed, with and without adjustment for diuretic therapy, creatinine clearance and age. Serum uric acid levels, whether adjusted or not for these variables and for body mass index, were positively associated with alcohol intake (men) and consumption of meat and fish (women), and inversely with consumption of bread, margarine and milk products (women). These results indicate that limited medication with diuretics, weight control and restriction of alcohol use may help to prevent hyperuricemia in the elderly.

Comparison of the inhibition of dietary fat absorption by full versus divided doses of orlistat.

Orlistat is a potent and selective inhibitor of gastrointestinal lipases. The drug is designed for the treatment of obesity. The effect on dietary fat absorption of orlistat after administration of divided doses spread over 2 hours from mid-meal, in comparison with that after administration of a full dose mid-meal, was investigated in a randomized, single-blind study including 16 hospitalized healthy males. After a 5-day run-in, to accustom the subjects to a diet of 2350 kcal and 76 g fat per day and to establish baseline fecal fat excretion, subjects received, in two parallel groups of eight over 8 days, three times a day 80 mg orlistat at mid-meal, and placebo at mid-meal and 0.5, 1, and 2 hr after mid-meal (group A), or placebo at mid-meal, and 20 mg orlistat at mid-meal and 0.5, 1, and 2 hr after mid-meal (group B). Feces were collected to measure total fat excretion. The mean (SD) of fecal fat in percent of dietary fat, after deduction of pretreatment fecal fat, was (%) 36.1 (4.2) and 37.0 (9.3) in groups A and B, respectively. Changing the mode of administration of orlistat, within the dose regimens investigated, does not affect its pharmacologic efficacy.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Release of platelet Met-enkephalin, but not serotonin, in migraine. A platelet response unique to migraine patients?

Plasma-induced release of platelet-serotonin and Met-enkephalin was studied by incubating platelets from migraineurs, tension headache patients and healthy volunteers with water, plasma collected during migraine attacks and with plasma collected during attack-free periods. Migraine-attack plasma, but not migraine attack-free plasma, released Met-enkephalin from platelets of migraineurs. Platelets of healthy controls or tension headache sufferers did not release their Met-enkephalin in response to either incubation medium. In contrast to Met-enkephalin, serotonin was not released from platelets in relevant quantities by migraine-attack plasma.

High-performance liquid chromatographic determination of urinary free catecholamines with electrochemical detection after prepurification on immobilized boric acid.

A reliable high-performance liquid chromatographic method is presented for the determination of the urinary free catecholamines noradrenaline, adrenaline and dopamine. Urine is purified on a column of immobilized boric acid. Catecholamines are separated by ion-pair reversed phase high-performance liquid chromatography and detected electrochemically. The method is suited for routine analysis. It allows the determination of urinary free catecholamines in concentrations as low as 1 microgram/1 for noradrenaline and adrenaline and 5 micrograms/1 for dopamine. A single analysis can be completed within 1 h. Routine analyses can be carried out in a series of 40 samples within 2 days. The within-assay and between-assay coefficients of variation of the analyses in urine were both 2.9% for noradrenaline, both 5.0% for adrenaline, and 1.9 and 2.1% for dopamine. The chromatographic properties of the immobilized boric acid were investigated. In particular, the elution pattern of a series of catecholamine metabolites and analogues was determined. Under the conditions used, only basic compounds containing both a vicinal hydroxyl configuration and a primary or secondary amino group adsorb and elute together with the free catecholamines.

Amino acids and glucose in human cerebrospinal fluid after acute ischaemic brain damage.

In the search for potential biochemical markers of value for prognosis after acute hypoxic brain damage, amino acids and glucose were assessed in the cerebrospinal fluid (CSF) and glucose in blood. Samples were taken by lumbar puncture 4, 28, 76 and 172 h after resuscitation from 20 patients and once from 10 control patients. Eight of the resuscitated patients recovered neurologically but 12 remained comatose. The concentrations of alanine (P less than 0.001) and phenylalanine (P less than 0.035) differed most in 4-h samples between the groups. The concentration of alanine was higher in all patient groups with hypoxic brain damage as compared to the controls, the concentrations in patients dying within 76 h (disabled-s group) being higher than in the recovered patients. Phenylalanine in the disabled-s group was significantly higher than the control value. Furthermore, there were significant differences between various patient groups in the concentrations of glutamine, isoleucine, leucine, lysine, serine, tyrosine and valine. When taking into account the permeability of the BBB to these amino acids, alanine, valine and isoleucine most clearly represent brain amino acid metabolism. CSF glucose in the control group and in the recovered patients was lower than in patients dying within 76 h.

Iodide excretion before and after revision of goiter prophylaxis (Dutch Nutrition Surveillance System).

To assess the iodine supply in The Netherlands after the revision of the goiter prophylaxis measures (Bread Act of 1982, with an increase of iodine content of bread salt) the data of a nationwide survey among Dutch elderly people conducted in 1984/1985 were analysed. Iodide excretion in 24 h urine samples was used as the main iodine status indicator. The data were compared with data on iodine nutriture obtained among an elderly population in The Netherlands before the revision of goiter prophylaxis. High prevalences (greater than or equal to 37%) of low iodine excretion (less than 0.78 mumol/24 h; 100 micrograms/24 h) were found for Dutch elderly people. Mean urinary iodide excretion was 0.95 mumol/24 h (121 micrograms/24 h) for men and 0.79 mumol/24 h (100 micrograms/24 h) for women which is low, especially among women, in comparison with the United States recommended dietary allowance (118 mumol/day = 150 micrograms/day). Consistent positive associations of iodide excretion were found with urinary potassium and sodium excretion, bread consumption and total iodine intake. Bread, as the iodine carrier chosen for goiter prophylaxis in The Netherlands, was found to be the main dietary iodine source. No improvement in iodine nutrition was found among the elderly studied in 1984/1985 in comparison with an elderly population seen in 1981. Therefore, it is concluded that the present measures regarding goiter prophylaxis in The Netherlands might be of limited effectiveness.

Food preferences and aversions and dietary pattern in anorexia nervosa patients.

Food intake, meal frequency and occurrence of vomiting and purging were assessed in 20 female patients with anorexia nervosa (AN) by two dietitians by means of a dietary history over the past month. Ten lean healthy women and 10 of normal weight served as two groups of controls. Two self-administered questionnaires, consisting of 51 questions each were developed and applied: one to get an insight into food preference and food aversion, another to evaluate the dietary pattern. A significant difference in energy intake was found between the patient group and both control groups, but not between the two control groups. Self-induced vomiting and weekly laxative use was only mentioned by the patients with AN. Between the patients and the controls significant differences were found in preference and aversion for several food products such as sugar, potatoes, meat, dates and bananas as well as in eating habits. Stepwise discriminant analysis of the data of the two questionnaires resulted in eight food items and three dietary pattern statements which specify group differences. It is concluded that the questionnaires used reveal important differences between anorexia patients and control subjects in attitudes towards foodstuffs, and can be a useful tool for early diagnosis when validated in larger samples of patients and controls.

Nutritional status in anorexia nervosa: clinical chemistry, vitamins, iron and zinc.

Routine clinical chemical variables and parameters of the vitamin, iron and zinc status were measured in 20 female patients with anorexia nervosa (AN) and in 10 lean and 10 normal weight, healthy, female control subjects. Patients with AN had higher activities of L-gamma-glutamyl transferase (gamma-GT) and glutamate pyruvate transaminase (SGPT) and a higher concentration of prealbumin in serum and lower leucocyte and lymphocyte counts in blood. For the other routine clinical chemical parameters no significant differences between the groups were observed. AN patients had higher serum vitamin B12 and retinol levels. No significant differences were found for the status parameters of thiamin, vitamin B6, vitamin C, folate, vitamin E and vitamin D. Contradictory results were obtained for the riboflavin status: AN patients had a lower level of flavin adenine dinucleotide (FAD) in blood and a lower stimulation ratio of the glutathione reductase activity in erythrocytes (alpha-EGR). Patients with AN had higher serum ferritin concentration and lower total iron binding capacity (TIBC). However, haemoglobin (Hb), haematocrit (Ht) and iron saturation were not significantly different. No significant difference was found in the concentration of zinc in plasma. In spite of the poor intake of nutrients and energy, the results obtained did not indicate an inadequate status of vitamins, iron and zinc in patients with AN.

Type A behaviour, borderline hyperventilation and psychological, psychosomatic and neuroendocrine responses to mental task load.

Psychological, psychosomatic and neuroendocrine (in blood) responses to mental task load were investigated in relation to Type A behaviour and borderline hyperventilation. For this purpose 32 apparently healthy, male volunteers were classified on the basis of their scores on the Jenkins Activity Survey (JAS) and on a questionnaire assessing hyperventilation related symptoms (HRS). The subjects performed a memory search task in which a monetary bonus could be won or lost. At rest higher HRS scores were related to increased acute psychosomatic symptom scores and higher JAS scores to higher prolactin levels. Task performance caused an increase of state anxiety, acute psychosomatic symptoms, adrenaline and cortisol, whereas prolactin decreased. Higher JAS scores were related to greater cortisol responses and higher HRS scores to smaller adrenaline responses.

Direct chemical ionization-mass spectrometric profiling of urine in premenstrual syndrome.

In search of the pathophysiological background of premenstrual syndrome, direct chemical ionization-mass spectrometric profiling was applied to urine samples from 17 patients and 18 control subjects, collected on days 11 and 25 of the menstrual cycle. Oestrogenic compounds and hippuric acid were found to be involved in differences between these groups. Quotient profiles calculated for each subject from their profiles of days 11 and 25 showed cycle day-dependent group differences. Masses accounting for these differences between patients and control subjects indicate the involvement of unsaturated heterocyclic compounds in premenstrual syndrome.

Hematological and clinicochemical profiles of healthy swine and swine with inflammatory processes.

The hematological and clinicochemical profiles of healthy swine and swine with inflammatory processes were investigated. Blood was collected at slaughter and postmortem examination was performed to select healthy swine and swine with pleuritis, pneumonia or abscesses. In healthy swine, the values of several variables revealed significant differences between gilts, barrows and boars. This was caused predominantly by the values obtained for boars. Inflammatory processes altered the values of most variables investigated, particularly for erythrocyte sedimentation rate, hemoglobin and hematocrit, for the activity of alkaline phosphatase, and for concentrations of iron, phosphate, albumin and fibrinogen in plasma. Compared with healthy swine, differences were largest for swine with metastatic abscesses and swine with both abscesses and other pathological lesions; differences were less pronounced in swine with solitary abscesses and were minor in swine with pneumonia and swine with pleuritis. Porcine hematological and clinicochemical profiles reflect the degree of inflammation.

The influence of radiotherapy and chemotherapy on the vitamin status of cancer patients.

The influence of external abdominal irradiation and cytostatic therapy on the vitamin status was studied in patients with cancer of the uterus, bladder or prostate and in patients with malignant lymphoma. It was found that the vitamin status of these patients at the beginning of therapy in general was adequate, though vitamin A and vitamin D levels were reduced. During radiotherapy decreases of vitamin E, vitamin C, vitamin B12 and folic acid levels were observed. Chemotherapy caused a decrease of the folic acid levels after a few months. No clinical symptoms of vitamin deficiency were observed.

Influence of dietary composition on the inhibition of fat absorption by orlistat.

Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. The effect of orlistat on dietary fat absorption, when it was administered with diets differing in fibre content (high and low) and accessibility of fat (intra- and extracellular fat), was investigated in 32 hospitalized healthy males, according to an open, two-factorial study design. The subjects were randomly allocated to one of four parallel groups of equal size: A = intracellular fat, high fibre (28 g/day); B = extracellular fat, high fibre; C = extracellular fat, low fibre (9 g/day); or D = intracellular fat, low fibre. After a 5-day run-in period to accustom the volunteers to the standardized diet (2500 kcal and 84 g fat per day) and to establish baseline faecal fat parameters, they received 80 mg orlistat, three times daily mid-way through each meal for 8 days. Faeces were collected to measure total fat and free fatty acid excretions. The mean baseline-corrected excretion (% of dietary fat) in groups A, B, C and D, respectively, was 37.0, 30.4, 30.3 and 34.5 for total fat, and 6.5, 4.3, 2.6 and 3.9 for free fatty acids. The 95% confidence intervals for the difference between the means for high fibre and low fibre groups and for intracellular fat and extracellular fat groups, respectively, were 1.4 +/- 4.9 and 5.5 +/- 4.9 for total fat, and 2.2 +/- 3.1 and 1.9 +/- 3.1 for free fatty acids. The statistically significant difference (P < 0.05) in total faecal fat between intracellular fat and extracellular fat groups, in absolute terms < 5 g fat/day, was not regarded as clinically relevant. Under the conditions of this study, dietary fibre content and accessibility of fat had no relevant effect on the inhibition of fat absorption by orlistat.

Haematological and clinico-chemical profiles of barrows at the farm and at slaughter.

Haematological and clinico-chemical profiles of blood of healthy stress-resistant swine collected at the farm and at slaughter were determined to investigate whether values of blood variables can be used to establish stress. The values of most variables investigated showed highly significant changes. It is concluded that haematological and clinico-chemical values may be useful in studies to detect, quantify and reduce stress-provoking conditions in stress-resistant swine.