Evidence of high concentrations of melatonin in lateral ventricular cerebrospinal fluid of sheep.

In this study we examined the cerebrospinal fluid (CSF) for regional differences in the concentration of melatonin. Cerebrospinal fluid samples were collected at hourly intervals from either the lateral ventricle or the cisterna magna of nine Merino ewes and were compared against jugular plasma. The study revealed that the CSF of the cisterna magna and the lateral ventricle had temporal patterns of melatonin that were similar to those found in jugular plasma. However, the concentrations of melatonin within the CSF obtained from the lateral ventricle were one order of magnitude higher than those of the jugular plasma, as verified by gas chromatography and mass spectrometry, while the melatonin concentrations within the CSF obtained from the cisterna magna were comparable to those of the jugular plasma. The data from this study suggest that there may be regional differences in the concentration of melatonin within the CSF and indicate that this medium is an important route of transport for melatonin from the pineal gland to putative target tissues.

Effects of prior exposure to prolonged continuous light on the pattern of melatonin secretion in sheep held under continuous darkness.

To gain insight into the nature of the neural centre regulating melatonin production by the pineal gland we have measured hourly changes in plasma melatonin in 16 ewes held for 42-56 h under continuous darkness following a 28-day period of exposure to continuous light. Plasma melatonin was undetectable while animals were in constant light but increased to normal night time levels (120-2,200 pmol/litre) within 10 min of the onset of darkness in 14 out of the 16 ewes regardless of whether this occurred at 1,200 h (group 1) or 2,400 h (group 2). In four ewes melatonin secretion was maintained for approximately 36 h, indicating that the pineal gland remained responsive to a static stimulatory signal presumably emanating from the supra chiasmatic nucleus. In all ewes, melatonin secretion ceased at approximately 12 and or 36 h after the onset of darkness and did not require a separate zeitgeber. Although the increase and the decline of plasma melatonin levels were synchronized within groups 1 and 2, there were sufficient differences in the pattern of melatonin secretion between the groups to suggest that the regulatory mechanism had an intrinsic component. A hypothesis involving a diurnal change in sensitivity to circulating melatonin is advanced to explain the observed differences in the synchrony of melatonin secretion and the prolonged episodes of melatonin secretion.

Potential functions of plasma prorenin; regional activation and tissue extraction.

The fate of circulating inactive prorenin was examined in patients and volunteers. Prorenin was activated either by acid-dialysis with warming at pH 3.3 or with trypsin. The results were similar but omission of warming reduced the value by 13%. In 6 volunteers, 20 min forearm venous occlusion raised regional total (T) and inactive (I) plasma renin concentration (PRC) by 51% and 48% without change of active (A) renin. During intense forearm exercise the ratio APRC: IPRC did not change in muscle or skin venous blood. Body anaerobic exercise increased APRC 3.7-fold without change in IPRC. These procedures activate plasminogen but are without effect on prorenin. In 18 patient with stable angina, TPRC was lower in coronary sinus than arterial blood (p less than 0.001) but APRC was not affected. A-V differences were not detected across the leg. Prorenin is apparently stable in the circulation but extracted by the heart.

Phase delay of the rhythm of 6-sulphatoxy melatonin excretion by artificial light.

The purpose of this study was to investigate the effect of bright artificial light exposure on the rhythms of 6-sulphatoxy melatonin and cortisol excretion in urine. Six healthy males were exposed to light (greater than 3,000 lux) from 1900 to 0200 h (sunset 1928 h) on one occasion. The artificial light delayed the onset of 6-sulphatoxy melatonin excretion. On the next evening the onset of 6-sulphatoxy melatonin excretion in normal light/darkness was delayed by 1 h. The timing of the peak excretion of cortisol was not affected by the light treatment; however, cortisol excretion rate was maintained at a significantly higher rate in the morning and afternoon after the treatment. These results demonstrate the inhibitory action of high intensity light in humans and suggest that one 6-h period of extra light in the evening can phase delay the melatonin onset.

Growth retardation and renal osteodystrophy in children with chronic renal failure.

Height, expressed as standard deviation scores for chronological age and for bone age, was studied in relation to glomerular filtration rate, bone age delay, and bone histology in 47 children with chronic renal disease and GFR less than 80 ml/min/1.73 m2. In multiple regression in all 47 patients, only GFR and bone age delay significantly affected height; 40% of children were short (height standard deviation score less than -2) for chronological age, and 9% were short for bone age. Renal osteodystrophy, which only occurred at GFR less than 30 ml/min/1.73 m2, significantly affected height only in children with congenital renal disease and GFR less than 20 ml/min/1.73 m2. Although radiological and biochemical changes of renal osteodystrophy were seen more often in short children, histological bone disease occurred just as frequently in tall children as in short children. Thus much of the observed height retardation in chronic renal failure is associated with delayed skeletal maturation. In addition, although severe renal osteodystrophy may contribute to growth retardation in advanced renal failure, our data suggest that milder degrees of bone disease evident only on histological study cannot be implicated in the etiology of growth failure in chronic renal impairment.

Quantitative bone histology in children with chronic renal failure.

Quantitative bone histology (on undecalcified sections following double tetracycline labeling), radiographs, and biochemistry were studied in 47 children, ages 1 to 17 years, with glomerular filtration rates (GFR) below 80 ml/min/1.73m2. The earliest histologic change was an increased osteoid surface accompanied by increased osteoblast and tetracycline surfaces. However, significant bone disease (increased osteoclastic surface, fibrosis, increased osteoid area, increased mineralization lag time, and reduced tetracycline uptake at osteoid surfaces) occurred only at GFR below 30 ml/min/1.73m2. Radiographs and alkaline phosphatase were normal in 25% of children with significant bone disease; parathyroid hormone was increased in 48% of children without bone disease. Thus, these noninvasive investigations were poor predictors of disease presence. GFR was the most sensitive indicator because bone disease occurred only at GFR below 30 ml/min/1.73m2 and was present in all children with GFR below 20 ml/min/1.73m2. It was concluded that bone histology is required for early detection of bone disease and is an essential tool in experimental studies of renal osteodystrophy. However, because the level of GFR will indicate the presence or absence of bone disease in most children, bone biopsy can be avoided generally in clinical practice.