A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort.

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

Effects of morning phototherapy on circadian markers in seasonal affective disorder.

BACKGROUND: The suppression of melatonin by light at 00.30 hours has been shown to be greater in winter than in summer on patients with seasonal affective disorder (SAD) but not in matched normal controls. METHOD: In this study 12 patients with SAD and 12 matched normal controls were exposed to morning light therapy in the winter. Melatonin profiles and sensitivity to light were measured before and after treatment. RESULTS: The SAD but not the normal group showed a phase advance of melatonin rhythms in response to phototherapy. There was an association between phase position and phase shift in the SAD but not in the normal group. CONCLUSIONS: There may be instability of circadian rhythms in SAD mediated by a high-amplitude phase response curve, rather than a fixed phase abnormality as had been previously suggested. This instability may be secondary to impaired serotoninergic function in the afferent pathways to the suprachiasmatic nuclei.

Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls.

BACKGROUND: The aim was to investigate the secretion profile of melatonin and seasonal affective disorder before and after treatment with fluoxetine. METHOD: A six-week case-controlled study with repeated overnight blood sampling was conducted. Ten patients fulfilling the criteria for major depressive disorder, seasonal type, with a 29-item Hamilton Depression Rating Scale (HDRS) score of at least 20 were compared with ten age- and sex-matched healthy controls in a clinical laboratory. The effects of fluoxetine (20 mg/day) on the HDRS and melatonin concentration were measured. RESULTS: Fluoxetine significantly reduced melatonin levels in both groups. There was no significant difference in melatonin secretion between the groups. CONCLUSIONS: The effect of fluoxetine differs from tricyclics and fluvoxamine, both of which increase melatonin.

The effect of temazepam on melatonin secretion and light sensitivity.

Seven healthy male volunteers had their light sensitivity (melatonin suppression) and melatonin phase measured before and after treatment with temazepam (20 mg) for 7 days. Temazepam did not alter the circadian phase of melatonin secretion (the Dim Light Melatonin Onset, the timing of the peak of secretion), the total melatonin secretion nor the sensitivity of melatonin secretion to suppression by full spectrum light. This is an important negative finding which suggests that the short half-life benzodiazepine hypnotic temazepam does not confound tests of light sensitivity or melatonin phase.

Eicosanoid production by brain tumours in vivo--evidence for intracranial compartmentation.

Brain tumours produce prostaglandins in vitro; their in vivo production has been studied by determining the levels of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha and thromboxane B2 in tumour cyst fluid and ventricular CSF taken from 21 patients with a variety of intracranial tumours. The levels were high in tumour cyst fluid but there was no overall increase in ventricular CSF. Hence, brain tumours do not produce a consistent pattern of abnormality of eicosanoid concentrations in the ventricular CSF that would be useful for diagnosis. If brain tumours produce excess quantities of these prostaglandins in vivo as they do in vitro, these prostaglandins may be rapidly cleared by the cerebral microvasculature unless compartmentalized within a tumour cyst.

Effect of hydrocephalus on prostaglandins and thromboxane B2 in ventricular cerebrospinal fluid.

The concentrations of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha (prostacyclin metabolite), and thromboxane B2 were assayed in ventricular cerebrospinal fluid obtained from 28 patients with hydrocephalus (17 obstructive, 11 communicating). Seven patients received dexamethasone or hydrocortisone on the day of sampling. No patient received nonsteroidal anti-inflammatory compounds for 48 hours before sampling. The median values did not differ significantly between the two types of hydrocephalus or from the concentrations in lumbar cerebrospinal fluid obtained from patients without intracranial pathology during lumbar myelography for possible lumbar disc disease. Hence, there is no evidence that eicosanoids accumulate in the ventricles in hydrocephalus, and it is unlikely that they have a significant role in its symptomatology.

Oral nimodipine reduces prostaglandin and thromboxane production by arteries chronically exposed to a periarterial haematoma and the antifibrinolytic agent tranexamic acid.

The calcium antagonist nimodipine blocks the effects of many vasoconstrictors of cerebrovascular smooth muscle and may reduce the incidence of delayed cerebral ischaemia following subarachnoid haemorrhage though not necessarily by inhibiting the development of angiographic cerebral vasospasm. Post-haemorrhagic CSF contains abnormally large quantities of various eicosanoids that partly reflect enhanced production by cerebral arteries. Does nimodipine affect this process? The extra-arterial and intra-arterial production of PG6 keto-F1 alpha, PGE2, PGF2 alpha and TXB2 were measured in perfused common carotid arteries taken from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days. All rabbits were given the antifibrinolytic agent tranexamic acid to retard resolution of the clot, and half were given oral nimodipine (2 mg/kg/day) for 10 days. Nimodipine significantly reduced the extra-arterial production of TXB2 during the third and fourth hours of perfusion and, less consistently, the production of PGF2 alpha, PGE2 and PG6 keto-F1 alpha. Lutrol, the solvent for nimodipine, had no such effect.

Fluid balance and secretion of antidiuretic hormone following transsphenoidal pituitary surgery. A preliminary series.

Hyponatremia developing some days after transsphenoidal pituitary adenectomy is a treacherous complication of uncertain cause. Of 19 patients monitored in a pilot study at the Wessex Neurological Centre, plasma sodium fell below 125 mmol/liter in three patients at times ranging from 6 to 9 days postoperatively. One patient had evidence of inappropriate secretion of arginine vasopressin (AVP), and the other two probably had steroid insufficiency despite apparently adequate steroid cover. In a more detailed study, the fluid and sodium balance of a further 16 patients was monitored for 7 to 11 days following transsphenoidal surgery together with plasma cortisol, renin, and AVP concentrations. No patient became severely hyponatremic. Three developed partial diabetes insipidus. Two patients with Cushing's disease had evidence of postoperative corticosteroid insufficiency despite normal steroid protection. An inappropriately low plasma cortisol concentration was recorded in both. Plasma AVP concentrations did not show a delayed surge postoperatively. Delayed hyponatremia appears to occur most often in patients with hypoadrenalism, as glucocorticoid cover is decreased. It results from water retention combined with natriuresis, and is reversed by glucocorticoid treatment.

Arterial eicosanoid production following chronic exposure to a periarterial haematoma.

Cisternal and lumbar cerebrospinal fluid obtained some days following a subarachnoid haemorrhage contains abnormally large quantities of various prostanoids; some may be partly the result of abnormal production by the cerebral arteries. The extra-arterial and intra-arterial production of 6 oxo PGF1 alpha (prostacyclin metabolite), PGE2, PGF2 alpha and TXB2 were measured in perfused rabbit common carotid arteries taken both from normal rabbits and from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days using two techniques. Prostaglandin production by control arteries was highest during the first hour of perfusion but declined or increased marginally (PGE2) during the succeeding three hours. Arteries exposed to a periarterial haematoma for 7 days produced prostaglandins at a high rate throughout the 4 hours of study, and there was a progressive and marked increase in PGE2 production. The disproportionate increase in the cerebral vasoconstrictor PGE2 may reflect the inflammatory response which occurred in the adventitia of the vessels. Increased prostanoid production by cerebral arteries probably does contribute to the increased levels in CSF after subarachnoid haemorrhage.

Urinary screening for abnormalities of amino acid or mucopolysaccharide metabolism in patients in a hospital for the mentally handicapped in Wessex.

Urine from 348 patients of a hospital for the mentally handicapped in Wessex was screened for abnormalities of aminoacid and mucopolysaccharide excretion. Persistent aminoacid abnormalities were found in 16 patients: two had phenylketonuria and one a severe variant form of hyperphenylalaninaemia (dihydropteridine reductase deficiency). In at least nine of the other patients, the observed abnormality was probably a secondary phenomenon. Two patients excreted excessive amounts of a glycosaminoglycan identified tentatively as hyaluronic acid. The study also uncovered one undiagnosed diabetic and three patients with urinary tract infection.