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Clinical Clerkship↗
Biomedical subjects
J Seggie
Publications and source records attributed to J Seggie.
Glycine toxicokinetics: vitreous fluid concentration and visual impairment.
We report the results of kinetic experiments in sheep. Following systemic loading with 45 g glycine, plasma, cerebral spinal fluid (CSF), and vitreous fluid from the vitreous body of the eye were assayed for glycine concentrations. Mean baseline plasma, CSF, and vitreous glycine concentrations were 730, 46, and 191 mumol/L respectively. One hour after loading, values were 21292, 1103, and 1150 mumol/L respectively. During the succeeding 7 h plasma and CSF concentrations fell in parallel but remained above normal. In contrast the vitreous concentrations remained high and did not change significantly during the 7 h post-infusion period. Retinal glycine receptors may be particularly vulnerable to neurotoxic effects of glycine because of these pharmacokinetic properties.
Animals↗
Retinal pigment epithelium response and the use of the EOG and Arden Ratio in depression.
Supersensitivity to light in depression has been observed with both neuroendocrine and ophthalmological assessment methods. The biological defect underlying this abnormality may be localized in either the photoreceptors, the retinal pigmented epithelium, or some interaction of the two. The present study assessed responses of the retinal pigmented epithelium (RPE). All subjects underwent thorough ophthalmological and mood assessments. The electrooculogram (EOG) was used to measure standing potentials of the RPE in response to light and dark in 20 normal controls and 20 unmedicated depressed patients. Both groups were matched for age, sex, time of day for the procedure, and prior lighting history. Reproducibility of the EOG measure on two independent occasions for 13 control subjects had an intrasubject reliability coefficient of 0.70. The mean +/- SD Arden Ratio (light peak/dark trough) of the control group (2.13 +/- 0.42) compared to the depressed group (2.28 +/- 0.72) showed no statistical difference. There was, however, a significant difference between groups in response to darkness; depressed patients had a lower standing potential in the dark compared to controls, suggesting supersensitivity to light. No difference between groups was detected in standing potentials at baseline or in response to light. Supersensitivity to light in depression may be related to abnormal function of the RPE, but the inherent reliability of the EOG precludes the use of this instrument in pursuing this hypothesis.
Adult↗
The effect of lithium on pupillary response to pulses of light in sheep.
Administration of lithium carbonate to sheep in the dose range of 600-1800 mg/day resulted in a linearly described rise in lithium levels in plasma and red blood cells. In contrast to the rodent model but in agreement with the human condition, plasma lithium levels exceeded those of red blood cells. Polydipsia and body weight changes were not evident. At plasma levels of 0.70-0.8 mM/l, lithium attenuated the ability of the pupil to constrict in response to 30-sec pulses of light in the 25-150 microW/cm2 intensity range but not the ability to dilate in the dark. Thus, similar to observations in normal human volunteers and bipolar patients, lithium reduces sensitivity to light. The sheep is proposed as a useful model for studying the actions of lithium.
Animals↗
Antidepressant medication reverses increased sensitivity to light in depression: preliminary report.
1. Sensitivity to blue light was quantified using a Friedman Central Field Analyzer and the Dark Adaptation Threshold procedure. 2. Patients diagnosed as having a major depressive disorder using research diagnostic criteria had dark adaptation thresholds quantified after a 10 day drug wash out and again after antidepressant drug therapy. 3. Prior to drug treatment patients were significantly more sensitive to light than controls as measured by cone but not rod thresholds. 4. Following drug treatment both cone and rod thresholds were reduced in patients. In comparison to controls, drug treatment normalized cone threshold and reduced rod threshold in patients. 5. These data provide ophthalmological evidence for increased sensitivity to light in non medicated depressive disorder and a reduction in sensitivity following antidepressant drug therapy. 6. The possibility of altered retinal function and consequently the ability to perceive and use light for entrainment of circadian rhythm in affective disorder deserves further study.
Adaptation, Ocular↗
Effect of chronic lithium on sensitivity to light in male and female bipolar patients.
1. Sensitivity to white light was quantified in euthymic bipolar male and female patients maintained on long term lithium therapy and age and sex matched unmedicated controls. 2. The Dark Adaptation Threshold procedure was used to assess sensitivity of both the cone and rod photoreceptors to short pulses of light. 3. Male and female controls did not differ in sensitivity to light. 4. Male patients in comparison to both controls and female patients evidenced reduced sensitivity to light during the cone and rod portion of the dark adaptation procedure. 5. Female patients did not differ from controls on sensitivity to light. 6. Using these and other published data the results were interpreted as suggesting that lithium reduces sensitivity to light during adaptation to dark.
Adaptation, Ocular↗
Glycine inhibition of pupillary responses to pulses of light in conscious sheep.
The use of a 1.5% glycine solution as a bladder irrigant during surgical removal of the prostate has been associated with transient visual impairment. Glycine is thought to be an inhibitory retinal transmitter. Adult female sheep were infused with a 1.5% glycine solution to provide a dose of 0, 7.5, 15, 30, or 60 g of glycine. The volume control was a solution of dextrose and saline. The degree of constriction of the pupil in response to 30 seconds of bright light following dilation in the dark was used as an index of visual response. Observations were made before and 2, 4, 6, 12, 24, 48, 96, and 192 hours after a single infusion. Significant inhibition of pupil response to light but not to the dark was apparent following systemically administered glycine resulting in plasma levels over 5000 mumol/L. Inhibition of pupil response was paralleled by behavioral indices of visual impairment but not by changes in plasma sodium, potassium, chloride or osmolality. The duration of the effect was dose dependent with visual impairment following a single high dose of glycine being detectable five days later and long after glycine levels had returned to normal. However, the relationship between dose, time, and effect appears to be complex. It is important to note that the present observations occurred at plasma glycine levels frequently experienced in routine surgical practice. The finding that significant long term detrimental effects of glycine could be detected should evoke a re-evaluation of the use of glycine as an irrigating solution for surgical procedures and stimulate further investigation of the effects of glycine on retinal function and the ability to perceive light.
Animals↗
Lithium and the retina.
Recent interest in light therapy for depression has stimulated consideration of the nature of the biological defect in affective disorder. One line of thinking suggests that manic-depressive patients are supersensitive to light and that lithium may act by altering light sensitivity and hence entrainment of biological rhythms. This paper focuses on possible mechanisms whereby lithium may influence retinal physiology and the ability to perceive light. Preliminary data were generated using the Dark Adaptation Threshold procedure with a repeated measure protocol. When depressed and unmedicated the patient was found to have significantly lowered thresholds for light detection compared to control values. This supersensitivity was alleviated following lithium treatment. Data are interpreted as suggesting that some of the therapeutic effects of lithium are localized in the retina. It is proposed that: (1) lithium primarily alters the ability of the retina to detect light and not visual acuity; (2) lithium influences sensitivity to light by modulating the functional environment of the rod photoreceptors in the retina and (3) future research should focus on the effect of lithium on the function of rod photoreceptors and the pigmented epithelial cells in patients with affective disorder.
Dark Adaptation↗
Effects of antidepressants on entrainment of circadian rhythms.
1. Anti-depressant drugs alter the period of circadian rhythms under free running conditions. We have examined whether treatment with anti-depressants alters such rhythms under conditions of entrainment to a lighting cycle or following a phase advance of the lighting. 2. In the first experiment, following entrainment to a 10L:14D lighting schedule, male Long Evans rats were injected daily for three weeks, with either saline, desipramine or clomipramine at a dose of 10 mg/kg. Under these conditions, the resting circadian patterns of serum corticosterone and melatonin were not affected. 3. In a second experiment, male Wistar rats, adapted to a 12L:12D lighting cycle, were implanted with transmitters, permitting continuous recording of temperature. Animals were given chow supplemented with clomipramine or desipramine so that plasma clomipramine levels were within the normal therapeutic range for humans and desipramine levels were at 4-6 times the therapeutic range. After three weeks of drug treatment, the mean 24 h pattern of temperature was decreased and phase advanced by 72 min in the desipramine group compared to clomipramine or controls. Following a 6 h phase advance in the lighting cycle, the three groups responded differently. The clomipramine group evidenced the most rapid advance in the acrophase, equivalent to 6.9 h, while the saline and desipramine treated groups re-entrained significantly more slowly. 4. Clomipramine, given to achieve clinically meaningful blood levels, does not alter the circadian temperature rhythm under constant conditions of alternating light and dark, but significantly accelerates the rate of re-entrainment to a 6 h phase advance of the lighting schedule.
Animals↗
Bipolar patients taking lithium have increased dark adaptation threshold compared with controls.
Recent epidemiological studies of mania suggest that admissions correlate with length of day and sunlight. As well, seasonal affective disorder--a depression occurring in winter, is reported to respond to light therapy and it has been proposed that supersensitivity to light is a trait-marker of manic-depressive illness. Dark adaptation threshold (D.A.T.)--a measure of night vision--was assessed in 19 euthymic manic-depressive patients stabilized on lithium, and in 19 drug-free healthy controls. The D.A.T. was significantly raised in the patients taking lithium. It is concluded that lithium induces subsensitivity to light.
Adult↗
Renal retransplantation. The Johannesburg Hospital experience.
Between 1968 and 1985 108 renal retransplants were performed at Johannesburg Hospital; 102 patients received a second, 5 patients a third, and 1 patient a fourth kidney. The actuarial graft survival at 1 and 5 years is 52.8% and 40.5%. All retransplanted kidneys were obtained from cadaver donors. Factors that influence second graft survival are the period of survival of the previous graft, the use of cyclosporin A, the level of pre-sensitisation determined by preformed antibodies, the original disease (in particular diabetes and analgesic nephropathy) and the patient's sex. The results of retransplantation are not significantly different from those found in patients with first allografts; hence retransplantation is justified in those individuals whose previous donor kidney has ceased to function.
Adolescent↗
Lithium and rhythms of beta-adrenergic ([3H]CGP-12177) binding in intact rat retina, pineal gland, and hypothalamus.
A new assay technique for the determination of neurotransmitter binding in retinal fragments has been used to characterize and quantify beta-adrenergic receptors with the ligand [3H]CGP-12177. This assay allowed us to quantify beta-adrenergic receptors in the retina, pineal gland, and hypothalamus obtained from individual rats during a 10-hr period around the switch from light to dark under a 12-hr light/12-hr dark lighting cycle. A significant rhythm of beta-adrenergic binding was observed in the retina and pineal gland. These rhythms were abolished by chronic lithium treatment. In contrast to previous observations in whole brain preparations, lithium did not affect beta-adrenergic binding in brain tissue (hypothalamus) using this assay. Our data suggest that lithium may attenuate beta-adrenergic receptor down-regulation in pineal and retinal tissue. To the extent that this mechanism is important for the coding of information about light and dark in the environment, these observations might assist in our understanding of the clinical chronopharmacological properties reported for lithium.
Animals↗
Dysregulation of neuroendocrine crossroads: depression, circadian rhythms and the retina--a hypothesis.
The pathophysiology of depression and the mechanism of action of lithium and other antidepressant drugs involve alterations in circadian rhythms. These include changes in both the intrinsic rhythm of circadian oscillators and in the sensitivity of the retina to LIGHT. The retina in humans is the only photoreceptor for circadian entrainment. The retinal-hypothalamic-pineal axis is the essential pathway for neuronal entrainment of rhythms which use light as a phase cue. A common substance throughout this axis in many species is MELATONIN. Retinal melatonin has been implicated in regulation of the sensitivity of the retina to light. The hypothalamus, at THE NEUROENDOCRINE CROSSROADS, has a central role in the integration of neurotransmitters and hormones in circadian rhythms. DYSREGULATION of the hypothalamic-pituitary-adrenal, as well as -gonadal, axes has been documented in depressed patients. Abnormalities in circulating melatonin have also been found in patients with affective disorders. It is speculated that the availability of melatonin along the retinal-hypothalamic-pineal axis may have important implications in the genesis of affective disorders. More specifically--is there a latent biochemical defect which causes a phase shift and change in circadian rhythms of melatonin and/or other neurotransmitters in the retina which then alters the sensitivity of the retina to light (for the visible spectrum) which in turn desynchronizes all other biological rhythms thus disrupting mental well-being? We suggest that variations of retinal photosensitivity in humans can be measured by using a visual testing system, and that depressed patients might show changes in photosensitivity which could be corrected when treated with lithium and/or antidepressants. It is our working hypothesis that the primary defect in depression may be a change in retinal function, and that behavioural and neuroendocrine concomitants of this disorder are secondary events.
Circadian Rhythm↗
Differential responsivity of corticosterone and prolactin to stress following lesions of the septum or amygdala: implications for psychoneuroendocrinology.
Attempts to use neuroendocrine challenge tests to reflect suspected CNS dysfunction are popular, but frought with problems of interpretation. The dexamethasone suppression test of cortisol is thought to reflect limbic system function. Hormone responses to the triple bolus challenge test have also been reported to reflect limbic system dysfunction, but interpretation is dependent upon the hormone chosen for study. Challenge tests using prolactin have fallen out of favour because the final common pathway for its regulation lies outside the blood brain barrier. Thus, the ability of prolactin to reflect CNS and, specifically limbic system activity has been questioned. The present study undertook to determine corticosterone and prolactin responses in response to a variety of stimuli in rats that had selected limbic system damage following stereotoxically placed electrolic lesions. Surgical groups included: normal, sham-operated, septal lesion, cortico-medial amygdala lesion or baso-lateral amygdala lesion. All CNS damage was verified histologically. The stimuli chosen for neuroendocrine challenge were 3 minutes of exposure to, a novel environment, noise, ether vapour or cold water. These stimuli were chosen for their presumed level of neural input to the hypothalamic-pituitary axis. In the normal group, prolactin, but not corticosterone evidenced a differential response to the four stimuli. Following surgery, corticosterone responses to all stimuli were significantly influenced only in the septal lesion group. There was no interaction between the location of lesion with the type of stimuli used to elicit the corticosterone response. Prolactin, in contrast, evidenced significantly different responses depending on the location of the lesion, the type of stimulus and an interaction of these two variables. This level of differential responsiveness suggests that prolactin may have potential for diagnosis of limbic system dysfunction if appropriate test stimuli are employed to elicit its response.
Adrenal Cortex Hormones↗
Lithium and circadian patterns of melatonin in the retina, hypothalamus, pineal and serum.
Lithium, a widely used substance for treatment of manic-depressive illness has been reported to alter the phase relationship of a variety of circadian rhythms which have been implicated in the aetiology of depression and manic-depressive disorder. Although its mechanism of action is not understood, the theraputic action of lithium has been related to its ability to alter circadian rhythms. Chronic lithium administration to rats resulted in lithium levels comparable to the human theraputic range. These lithium levels affected a broad range of biological variables by significantly modifying their circadian pattern of variation, notably during the dark period of an alternating 12h light/12h dark schedule. These included water intake, body weight, retina weight and pineal, serum, retina and hypothalamic melatonin measures. Retinal lithium levels were significantly higher than serum lithium levels and retinal melatonin levels were reduced by lithium. The data are interpreted as suggesting that lithium may exert its theraputic effects by influencing melatonin levels at several locations along the retinal-hypothalamic-pineal pathway, resulting in a modulation of the potential cue value of this physiological stimulus for synchronization of circadian rhythms. Such an effect of lithium could have important chronobiological implications for circadian rhythms which use light and dark as a phase cue.
Animals↗
Effects of fornix transection and pituitary-adrenal modulation on extinction behavior.
We examined whether the absence of a dynamic pituitary-adrenal response contributes to the behavioral deficit seen in hippocampally damaged rats following the transition to extinction of a learned behavior. In the first experiment, total lever presses and detailed behaviors of rats with fornix transection and replacement ACTH4-10 or ACTH were compared with the behavior of fornix-transected and sham-transection groups during acquisition and extinction of lever pressing. Fornix-transected rats showed increased resistance to extinction and an altered pattern or mode of extinction responding. ACTH4-10 or ACTH acted similarly in reducing extinction lever presses in fornix-transected rats without altering the mode of extinction responding. In the second experiment the extinction behaviors of rats with fornix transection were compared with those of normal, sham-transection adrenalectomized, or dexamethasone-treated rats. Fornix-transected rats again showed increased resistance to extinction and a different mode of responding during extinction. Adrenalectomized rats showed an extinction deficit but differed from fornix-transected rats. The behavior of dexamethasone-treated rats was similar to that of controls. The results are interpreted to mean that ACTH and corticosterone both affect extinction behavior (in opposite ways) but do not account for the extinction deficit seen in hippocampally damaged rats.
Adrenocorticotropic Hormone↗
Transplantation of kidneys from related living donors at Johannesburg Hospital.
The Johannesburg Hospital kidney transplantation unit's experience with 111 kidney donations from living relatives between 1966 and December 1984 is reviewed. The 1-year patient survival rate for those who received transplants up to the end of 1982 was 93%. Donor surgery only caused 1 instance of serious illness and no deaths. The justification for and procedure of donor transplantation are discussed and the psychological reward to the donor highlighted.
Adult↗
Renal function after nephrectomy for donor organs.
Thirty-three living related kidney donors were investigated at a mean of 5.8 years after donor nephrectomy (range 3-18 years) to detect late adverse effects. They were evaluated for hypertension, the presence of proteinuria and renal dysfunction as assessed by serum creatinine value and creatinine clearance. There was a significant rise in both diastolic blood pressure and serum creatinine levels and a trend towards significance in the decline in creatinine clearance. Eleven individuals had diastolic blood pressure greater than or equal to 90 mmHg but only 1 required treatment. Although the rise in serum creatinine reached significance the mean serum creatinine (104.91 mumol/l) remained within the normal range. Two patients showed a minimal rise in proteinuria. The overall results confirm that kidney donation is safe and indicate that there are no significant late sequelae.
Adult↗