Circadian rhythms are known to be entrained to the 24 hour day through interactions between endogenous mechanisms and a number exogenous factors that include the light-dark cycle and social interaction. Intensive care patients are thought to be prone to disturbances in their circadian rhythms due to isolation from environmental changes and sensory deprivation as a result of sedation and sleep disturbance. The main aim of this thesis was to determine whether circadian rhythms in critically ill patients are desynchronised from the environment in comparison with those observed in healthy individuals, using urinary aMT6s excretion, plasma melatonin and core body temperature as markers of the endogenous clock. Patients in the Intensive Care Unit (ICU) at the Royal Free Hospital, London, who were stable, inotrope-free, not undergoing haemodiafiltration and with an ICU stay of more than three days were studied. Cosinor analysis of retrospective core body temperature data taken from nursing charts showed that a statistically significant rhythm with a period of 24h was present in 49.5% of the patient days studied. The position of acrophase showed abnormalities within individuals and between individuals. Prospective core body temperature studies confirmed the findings of abnormal circadian rhythmicity but suggested that the rhythms were influenced by fever associated with infection. Urinary 6-sulphatoxymelatonin (aMT6s) excretion data detected rhythmic activity and allowed for the identification of four patterns of excretion rate over 24h: normal rhythmicity, phase shifted rhythms, abnormal with frequent fluctuations and abnormal but arrhythmic. Urinary aMT6s excretion rate measured on two or three occasions at weekly intervals identified changes associated with the normalisation of circadian rhythmicity, namely an increase in the amplitude in some patients and the development of significant diurnal changes from grossly abnormal patterns of urinary aMT6s excretion in others. This trend was seen in patients that were improving clinically, but could not be associated with disease severity as determined by APACHE II scoring. Studies on the circadian rhythms of urine volume and creatinine clearance suggested that renal function in the absence of acute renal failure was still impaired or possibly influenced by treatment medication and could modify urinary aMT6s excretion. Measurements of plasma melatonin identified circadian rhythmicity in 7 out of 9 patients of which 5 were significant by cosinor analysis. These 5 patients had plasma melatonin rhythms that were either normal or phase shifted. The circadian rhythms of plasma cortisol, plasma prolactin and plasma TSH in most ICU patients were also abnormal and showed poor correlations with plasma melatonin. Overall this thesis provides evidence of abnormal circadian rhythmicity in critically ill patients and identifies this group of patients as one that might benefit from light or melatonin treatment to help resynchronise rhythms.

Melatonin is a hormone secreted by the pineal gland, which is known to modulate biological rhythms in mammals. This study investigated the effect of food access schedule and dietary composition on serum melatonin and pineal NAT activity in adult male Wistar rats. These rats were maintained on a 12:12 h light:dark schedule with lights on at 0800h. The rats were randomly assigned to two dietary groups. A group was simultaneously fed a protein-rich and carbohydrate-rich granulated diet and the other group fed granulated rat chow. Each dietary group was further divided based on dietary feeding schedules. Animals were fed between 0800--1600 h or fed ad libitum. The study revealed that protein intake of rats fed the dietary choice was lower with the restricted access than in the free access. In rats fed dietary choice, the nocturnal melatonin levels and pineal NAT activity were significantly lower under the restricted access feeding when compared to the ad libitum feeding schedule. This was not observed in rats fed single chow diet. In conclusion our data demonstrate that food composition does affect the nocturnal synthesis of melatonin as well as the activity of the enzyme NAT. This could be via dietary intake of tryptophan, which is a precursor melatonin synthesis in the pineal gland.

No description available.

A glândula pineal produz melatonina, estimulada pela liberação noturna de noradrenalina na pineal. O exercício físico aumenta a atividade dos neurônios simpáticos periféricos e a noradrenalina, o que modularia a síntese de melatonina. Porém há controvérsias, pois viu-se o aumento, a diminuição e a não alteração da síntese de melatonina induzida pelo exercício. Ademais, o diabetes induzido e o envelhecimento reduzem a síntese de melatonina pineal em ratos. Dessa maneira avaliou-se os efeitos do treinamento físico aeróbio sobre a síntese desse hormônio sob várias condições: animais adultos, diabéticos não tratados e idosos, sendo eles sedentários ou treinados. Nos adultos treinados não houve diferença na produção de melatonina, nos diabéticos não foi vista alteração na atividade da enzima AANAT e nos idosos treinados houve aumento na atividade da AANAT e na expressão gênica do receptor β adrenérgico no ZT18. Em suma, o treinamento físico não alterou a síntese de melatonina nos animais adultos e nos diabéticos, mas foi capaz de modulá-la nos animais idosos treinados. / The pineal gland produces melatonin stimulated by the nocturnal release of norepinephrine. Physical exercise increases the activity of peripheral sympathetic neurons and norepinephrine release, which may modulate melatonin synthesis. Melatonin synthesis modulation by exercise remains controversial. On the other hand, induced diabetes and aging reduce the pineal melatonin synthesis. In this way, we assessed the effects of aerobic exercise training on the synthesis of this hormone under various conditions: adult, untreated diabetic and aged animals, either sedentary or trained. Physical exercise did not alter melatonin production in adult rats and diabetic ones showed no AANAT enzyme activity change. Trained aged animals presented no increase in AANAT activity and β-adrenergic receptor gene expression at ZT18. In conclusion, physical training did not alter melatonin synthesis in adult animals and in diabetic ones but was able to modulate it in trained aged animals.

Bibliography: leaves 89-118 / viii, 118 leaves : ill ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1987

A glândula pineal produz melatonina, estimulada pela liberação noturna de noradrenalina na pineal. O exercício físico aumenta a atividade dos neurônios simpáticos periféricos e a noradrenalina, o que modularia a síntese de melatonina. Porém há controvérsias, pois viu-se o aumento, a diminuição e a não alteração da síntese de melatonina induzida pelo exercício. Ademais, o diabetes induzido e o envelhecimento reduzem a síntese de melatonina pineal em ratos. Dessa maneira avaliou-se os efeitos do treinamento físico aeróbio sobre a síntese desse hormônio sob várias condições: animais adultos, diabéticos não tratados e idosos, sendo eles sedentários ou treinados. Nos adultos treinados não houve diferença na produção de melatonina, nos diabéticos não foi vista alteração na atividade da enzima AANAT e nos idosos treinados houve aumento na atividade da AANAT e na expressão gênica do receptor β adrenérgico no ZT18. Em suma, o treinamento físico não alterou a síntese de melatonina nos animais adultos e nos diabéticos, mas foi capaz de modulá-la nos animais idosos treinados. / The pineal gland produces melatonin stimulated by the nocturnal release of norepinephrine. Physical exercise increases the activity of peripheral sympathetic neurons and norepinephrine release, which may modulate melatonin synthesis. Melatonin synthesis modulation by exercise remains controversial. On the other hand, induced diabetes and aging reduce the pineal melatonin synthesis. In this way, we assessed the effects of aerobic exercise training on the synthesis of this hormone under various conditions: adult, untreated diabetic and aged animals, either sedentary or trained. Physical exercise did not alter melatonin production in adult rats and diabetic ones showed no AANAT enzyme activity change. Trained aged animals presented no increase in AANAT activity and β-adrenergic receptor gene expression at ZT18. In conclusion, physical training did not alter melatonin synthesis in adult animals and in diabetic ones but was able to modulate it in trained aged animals.