Loss of normal circadian profile of urine excretion in idiopathic restless legs syndrome

BACKGROUND: This study was performed to elucidate preliminary observations of excessive nighttime urine excretion in idiopathic restless legs syndrome (iRLS). METHODS: Seventeen patients, with normal serum creatinine, blood urea nitrogen, and urate, and 11 healthy controls were examined. We measured excretory renal function parameters (urine volume, osmolarity, sodium, chloride, potassium, calcium, phosphate, microalbumin, aldosterone, creatinine) between 7:00 am and 10:00 pm and between 10:00 pm and 7:00 am. RESULTS: During the nighttime, volume (P=0.006), sodium (P=0.009), and chloride excretion (P=0.001) were significantly higher, and osmolarity (P=0.025) was significantly lower in patients as compared to controls. In comparing daytime to nighttime, controls showed the physiological reduced nocturnal excretion of volume (P=0.009) and chloride (P=0.023), and an increased osmolarity (P=0.026), but patients showed similar excretion rates of these parameters (all differences ns). CONCLUSIONS: These data indicate a loss of normal circadian profile of urine excretion in iRLS. The elevated nighttime excretion, with values similar to those in the daytime, hint at a possibly elevated fluid, sodium, and chloride intake during daytime.     

Urinary catecholamines and mitral valve prolapse in panic-anxiety patients

Free norepinephrine and epinephrine were measured in two consecutive 12-hour urine collections gathered during normal activity and sleep from 23 panic-anxiety patients and 9 normal subjects. Mitral value prolapse (MVP) was found in 7 of 20 patients who had echocardiograms. Mean nighttime norepinephrine and epinephrine excretion in panic-anxiety patients without MVP was significantly higher than that of control subjects, and was significantly higher than that of anxiety patients with MVP. In the daytime, all groups had higher catecholamine (CA) levels, but the differences between the groups were less pronounced. Medication significantly relieved symptoms and was associated with decreased CA levels. Elevated basal CA levels may characterize the subgroup of panic-anxiety patients who do not have MVP.     

Debrisoquine oxidation in Parkinson''s disease

Variations in the activities of xenobiotic metabolizing liver enzymes may be involved in the pathophysiology of diseases, including Parkinson's disease. We therefore studied the activity of the debrisoquine metabolizing enzyme in 97 patients with newly diagnosed Parkinson's disease. The urine debrisoquine metabolic ratios (MR) of the patients were compared with a group of 176 healthy subjects. There were 4 poor metabolizers (4.1%) among the parkinsonians. This proportion did not differ from that found in the group of healthy subjects (51%). In contrast to earlier finding, the parkinsonian poor metabolizers (PM) had the onset of the disease later than the parkinsonian extensive metabolizers (EM). In the parkinsonian patients, it was observed that the excretion of debrisoquine and 4-OH-debrisoquine into urine correlated inversely with the actual age and age at disease onset. Our results indicate that in patients with Parkinson's disease, debrisoquine hydroxylation is comparable with healthy subjects.     

Psychiatric illness in a general urban emergency room: daytime versus nighttime population.

Two hundred adults presenting to the emergency room of an urban general hospital were interviewed by a standardized technique to evaluate the existence of a current or previous psychiatric illness. Half of the subjects presented between 8:00 a.m. and 4:00 p.m. (daytime group), and 100 presented between 12:00 a.m. and 8:00 a.m. (nighttime group). In the nighttime population 65% were judged to have current or past psychiatric illnesses. In the daytime population only 36% had current or past psychiatric illnesses. The differences between the 2 populations was highly significant. Fewer than 10% of the 200 patients presented with neuropsychiatric symptoms in their chief complaints.     

Effect of hydantoins on urinary excretion of 5-hydroxyindoleacetic acid

The investigations were carried out in 10 patients with epileptic seizures. The obtained results were compared with those in a control group of 20 healthy subjects. The 24-hour urinary excretion of 5-HIAA efore hydantoinal and on the 1st, 2dn and 3rd days of hydantoinal administration was determined by the method of Udenfried et al. as modified by McFarlane et al. It was found that healthy subjects excreted significantly more 5-HIAA before and after hydantoinal load. Administration of this drug increased significantly the excretion of this metabolite with urine, in healthy subjects but in epileptics it had no significant effect on 5-HIAA level in 24-hour urine.     

Daytime sleeping, sleep disturbance, and circadian rhythms in the nursing home.

OBJECTIVE: This study reports the frequency of abnormal daytime sleeping and identifies factors related to daytime sleeping, nighttime sleep disturbance, and circadian rhythm abnormalities among nursing home residents. METHODS: The authors conducted secondary analysis of data collected under usual care conditions within a nonpharmacologic sleep intervention trial. All residents from four Los Angeles nursing homes were screened for daytime sleeping (asleep>or=15% of observations, 9:00 am-5:00 pm). Consenting residents with daytime sleeping had two nights of wrist actigraphy to assess nighttime sleep disturbance (asleep<80%, 10:00 pm-6:00 am). Residents with nighttime sleep disturbance completed an additional 72-hour wrist actigraphy recording to assess circadian activity rhythms and light exposure. RESULTS: Sixty-nine percent of 492 observed residents had daytime sleeping, of whom 60% also had disturbed nighttime sleep. Sleep disturbance and daytime sleeping were rarely documented in medical records. Residents spent one-third of the day in their rooms, typically in bed, and were seldom outdoors or exposed to bright light. More time in bed and less social activity were significant predictors of daytime sleepiness. Ninety-seven percent of residents assessed had abnormal circadian rhythms. More daytime sleeping and less nighttime sleep were associated with weaker circadian activity rhythms. Later circadian rhythm acrophase (peak) was associated with more bright light exposure. CONCLUSION: Daytime sleepiness, nighttime sleep disturbance, and abnormal circadian rhythms were common in nursing home residents. Modifiable factors (e.g., time in bed) are associated with sleep/wake abnormalities. Mental health specialists should consider the complexity of factors causing sleep problems in nursing home residents.     

Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84

Although the hormone melatonin is a key factor for the proper functioning of the circadian timing system (CTS) and exogenous melatonin has been shown to be beneficial in cases of CTS disturbances, a deficit of melatonin has yet to be defined as a disorder. The aim of our study was to collect a normative data set on 24-h melatonin excretion in healthy human adults living in a natural environment. Urine samples were collected from 75 healthy subjects (45 women/30 men; mean age 47.2, SD 19.5, range 20-84) after five consecutive periods: 2300-0700, 0700-1100, 1100-1800, 1800-2300 and 2300-0700 h. 6-Sulfatoxymelatonin (aMT6s) concentrations were analyzed in duplicate by IBL (Hamburg) using a highly sensitive, competitive ELISA kit. Twenty-four hour-aMT6s total amount (rho=-0.68, p<0.001), aMT6s nighttime excretion (rho=-0.69, p<0.001), aMT6s morning excretion (rho=-0.66, p<0.001) and evening excretion (r=-0.26, p=0.023) were negatively associated with age, whereas daytime excretion (r=-0.17, p=0.15) was not. The intra-subject night-day ratio varied up to 10.5 (mean 6.0) in young subjects (aged 20-35) and up to 5.4 (mean 2.8) in older individuals (age>65). The total amount of 24 h-aMT6s (range 7.5-58 microg) as well as the amount of aMT6s excreted during the nighttime period (range 327-6.074 ng/h) varied as much as 20-fold between individuals. Our data show an age-related decline in melatonin excretion in healthy subjects living in a natural environment. The high inter-individual variability of excretion rates may explain why a normative data set is of no use in replacement strategies.     

A quantitative study of daytime sleepiness induced by carbamazepine and add-on vigabatrin in epileptic patients

Introduction – The clinical relevance of daytime sleepiness associated with carbamazepine (CBZ) and vigabatrin (VGB) was objectively assessed by the multiple sleep latency test (MSLT) and nocturnal sleep recordings. Material and methods – Twenty-six patients with partial epilepsy and mean monthly seizure frequency of 4, aged 18 to 48 years, receiving chronic monotherapy with CBZ and subsequent VGB addition for 2 months (14 patients), were compared with a group of healthy subjects. Subjective daytime sleepiness was complained by 13 patients on CBZ monotherapy and 9 patients during VGB add-on treatment. Results – No differences in nocturnal sleep parameters, but significantly shorter daytime sleep latencies at the MSLT, were detected in CBZ-treated patients as compared with healthy controls. Addition of VGB therapy did not further enhance objective daytime sleepiness. Conclusion – Some sleepiness occurs in chronically CBZ-treated epileptic patients, which can be objectively measured by the MSLT, but it is not aggravated by add-on VGB.     

Sulphatoxy melatonin: an index of depression in anorexia nervosa and bulimia nervosa

Urinary excretion of the principal melatonin metabolite, sulphatoxy melatonin (aMT6s), was assessed both during the day and during the night in 38 female eating disorder patients (anorexia nervosa, n = 17; bulimia nervosa, n = 12; anorexia nervosa + bulimia nervosa, n = 9) and 14 female control subjects. Correlations between nocturnal serum melatonin and urinary aMT6s were also obtained. All patient groups and the controls showed a preservation of diurnal rhythm with elevated nocturnal urinary aMT6s values and no significant difference in amplitude between groups. However, patients with concurrent major depression had significantly lower levels of daytime and nighttime urinary aMT6s than the nondepressed group. Weight did not influence these findings. Correlations between nocturnal serum melatonin levels and urinary aMT6s were high for control subjects (r = 0.77) and moderate for the patient groups (r = 0.31). This may reflect differences in the rate of excretion of melatonin between patients and controls.     

Influence of mirtazapine on urinary free cortisol excretion in depressed patients

Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response.     

Cırcadian changes in cortical excitability in restless legs syndrome

Various investigations have revealed a widespread and somewhat controversial pattern of cerebral, cerebellar and brainstem involvement in the pathophysiology of restless legs syndrome (RLS). However, several studies which investigated functional or structural aspects indicated cortical involvement in RLS. In this study, we aimed to analyze circadian changes of cortical excitability in idiopathic RLS patients by means of transcranial magnetic stimulation (TMS). Eleven idiopathic RLS patients and eight healthy age and sex matched subjects were investigated using single-pulse TMS and motor nerve conduction studies during early afternoon when there were no symptoms and late at night (22:00-23:00) when the symptoms reappeared. Central motor conduction time, latencies and amplitudes of scalp and cervical motor evoked potentials, resting and active motor thresholds, and cortical silent period were measured. Measured parameters were similar between RLS patients and healthy subjects during the daytime. At night, cortical silent periods tended to shorten, and motor thresholds tended to decrease in the RLS group, whereas in controls they tended to increase. At night, active motor-threshold measurements were significantly lower in the RLS group (28.5 ± 6.2% vs 40.4 ± 8.4%, p=0.006). Therefore, we propose that in patients with RLS, conduction along the motor corticospinal axons is normal, with the possible loss of subcortical inhibition at nighttime.     

Effect of Felbamate on Valproic Acid Disposition in Healthy Volunteers: Inhibition of β-Oxidation

Summary: We assessed the effects of felbamate (FBM) on the disposition of valproic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2–4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2–en, 4–en, and 3–oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3–oxo and 4–hydroxy metabolites in urine, were measured by gas chromatography/mass spectrometry (GUMS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 μg/ml (1,200 mg dose) to 76.8 μg/ml (3,600–mg dose). Mean plasma VPA C_max values were 32–42 μg/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4–63.8 μg/ml). The excretion of 3–oxo–VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at ∼2400 mg/day. FBM had caused significant inhibition of the β-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.     

Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression

Objective: The hallmark symptom of fibromyalgia (FM) is widespread chronic pain, but most patients are also impaired due to fatigue and sleep disturbance, and there is a strong association with depression. We compared levels of activity and sleep patterns in FM patients, with and without comorbid depression, to those of normal healthy controls and depressed patients. Methods: Actigraphy was carried out on 16 patients with uncomplicated FM, 6 FM patients with comorbid depression, 9 patients with recurrent major depression, and 28 healthy controls over a period of 5–7 days. The means of daytime activity levels, nighttime activity levels, and percentage time spent asleep during the daytime and nighttime were calculated and compared. Results: Controls showed high levels of activity during the day and uninterrupted periods of sleep at night. Patients with FM alone showed similar levels of daytime activity, but disturbed sleep with significantly increased levels of activity at night compared to normal controls. Patients with depression alone also showed disturbed sleep compared to normal controls. However, patients with FM and comorbid depression showed the most impairment, with significantly reduced daytime activity and significantly increased daytime sleeping compared to controls, as well as more sleep interruption and movement during the night. Conclusion: Actigraphy is a useful means of studying activity levels and sleep patterns and demonstrated significant differences between FM patients with and without comorbid depression.     

Differential rates of urinary noradrenalin excretion in affective disorders: Utility of a short time sampling procedure

Levels of morning urinary noradrenalin (NA) excretion were compared in 61 patients with unipolar major depression (MDR), 25 patients with minor depression (mDE), 39 patients with anxiety disorder (AD), and 21 healthy control subjects (C). The following differences in the level of urinary NA excretion rate were found: MDE > mDE = AD > C. In addition, a significant positive correlation was found in the MDE group between severity of illness, expressed as total Hamilton depression score, in diagnostic subclasses from the Research Diagnostic Criteria, and urinary NA excretion rates (first episode, MDE total group, recurrent, with psychotic features). These data support the utility of a short time urine sampling procedure to measure NA excretion as a peripheral marker monitoring sympathetic activity in inpatient as well as outpatient conditions.     

Similarity of patterns of urine excretion among nonpolyuric and polyuric patients with thought disorders

From a study population of 29 institutionalized chronically psychotic patients, 70% of whom had schizophrenic or schizoaffective disorders, nonpolyuric and polyuric patients had similar diurnal patterns of urine excretion. Patients excreted a larger portion of daily urine volume after noon (55%) than before noon (45%).     

Abnormal heart rate variability in a subject with second degree atrioventricular blocks during sleep.

OBJECTIVE: We compare the profiles of heart rate variability (HRV) during sleep stages in 9 healthy controls and one subject with second degree atrioventricular blocks (AVB), investigating the role of sympathovagal balance in such pathology. METHOD: Sleep and cardiac records were taken for one night in 9 male subjects from 21:00 to 07:00 h and for two nights in a male subject with AVB. Time and frequency domain indexes of HRV were calculated over 5 min-periods. RESULTS: In one subject without any daytime heart disease, 253 and 318 AVB of type 2 (Mobitz 2) were observed during the two experimental nights, predominantly during rapid eye movement (REM) sleep and the surrounding sleep stage 2 in the second half of the night. In the 9 control subjects, absolute HRV indexes and low frequency (LF)/(LF+high frequency, HF) (where LF and HF are low frequency and high frequency power) were low during slow wave sleep, and significantly increased during REM sleep and the preceding sleep stage 2. In the subject with AVB, these HRV indexes were abnormally low during all sleep stages, with a predominant increase in parasympathetic activity as inferred from low LF/(LF+HF). During wake, however, LF/(LF+HF) normally increased, and the tachycardia observed with the arousal that terminates SWS was preserved in the subject with AVB. CONCLUSION: These results suggest that in the subject with second degree atrioventricular blocks, sleep processes, particularly during REM sleep, create a specific neurological background that prevents an increase in sympathetic tone and triggers cardiac pauses.     

Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion

Abstract  Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabelled. Urine was collected every 2 h from 0 to 8 h, and from 8 to 24 h. Two hours after LF, gastric residual was 15.9 ± 6.2% (SEM), and the percentage in colon was 49.6 ± 7.8%; in 11/12 participants, liquid had entered colon within 2 h. Average CAP arrival time in colon was 5.16 ± 0.46 h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8 h; lactulose absorption was low thoughout the 24 h. After the LF, the LMR (geometric mean, 95% CI per h) in the 0–2 h urine was [0.08 (0.05, 0.11)], which was lower than in 8–24 h urine [0.32 (0.16, 0.46); P  < 0.05]. Urine LMRs at 8–24 h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0–2 h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24 h. CAP delivery reduces mannitol excreted at 0–6 h, compared with LF. The 0–5 or 6 h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8–24 h urine relative to 0–2 h urine should be interpreted with caution and does not mean that colon is more permeable than SI.     

Urine concentration in depressive illness

A total of 132 urine specimens were obtained from 17 depressed patients and 18 controls under conditions of mild water deprivation. Mean values of milliosmoles of solute and millilitres of urine excreted per hour were obtained for each subject. The depressed patients excreted significantly less solute than the control group per unit volume of urine. There was no significant difference between the solute excretion rates of depressed patients and those who had recently recovered from depression—though the trend was towards normality. The significance of these results is discussed in relation to studies on body fluids and electrolytes and the role of ADH and aldosterone in affective disorders.     

Urinary phenylacetic acid excretion in depressive patients

Phenylacetic acid (PAA), a metabolite of phenylethylamine, has been found in the urine of depressed patients at lower levels than in control subjects. It has been suggested that the determination of PAA in urine could be used as a biological marker of the depressive condition. In this study the levels of PAA in urine were investigated by gas-liquid chromatography in 39 patients diagnosed as having major depression according to DSM-III criteria, and in 32 healthy subjects. The values found in the patients were markedly lower than in controls. No relationship was found between the decrease of PAA excretion and weight loss. Using a discriminant equation, a value of 69% was obtained for both sensitivity and specificity. The results suggest that the determination of urine PAA could be a biological parameter comparable to the dexamethasone suppression test.