Altered photic and non-photic phase shifts in 5-HT(1A) receptor knockout mice.

The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) is thought to be modulated by 5-HT. 5-HT is though to inhibit photic phase shifts by inhibiting the release of glutamate from retinal terminals, as well as by decreasing the responsiveness of retinorecipient cells in the SCN. Furthermore, there is also evidence that 5-HT may underlie, in part, non-photic phase shifts of the circadian system. Understanding the mechanism by which 5-HT accomplishes these goals is complicated by the wide variety of 5-HT receptors found in the SCN, the heterogeneous organization of both the circadian clock and the location of 5-HT receptors, and by a lack of sufficiently selective pharmacological agents for the 5-HT receptors of interest. Genetically modified animals engineered to lack a specific 5-HT receptor present an alternative avenue of investigation to understand how 5-HT regulates the circadian system. Here we examine behavioral and molecular responses to both photic and non-photic stimuli in mice lacking the 5-HT(1A) receptor. When compared with wild-type controls, these mice exhibit larger phase advances to a short late-night light pulse and larger delays to long 12 h light pulses that span the whole subjective night. Fos and mPer1 expression in the retinorecipient SCN is significantly attenuated following late-night light pulses in the 5-HT(1A) knockout animals. Finally, non-photic phase shifts to (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) are lost in the knockout animals, while attenuation of the phase shift to the long light pulse due to rebound activity following a wheel lock is unaffected. These findings suggest that the 5-HT(1A) receptor plays an inhibitory role in behavioral phase shifts, a facilitatory role in light-induced gene expression, a necessary role in phase shifts to 8-OH-DPAT, and is not necessary for activity-induced phase advances that oppose photic phase shifts to long light pulses.

Could do better: a curious clinician looks back--and forward.

A recently retired Scottish academic originally chose ophthalmology by a process of exclusion. Basic training in Glasgow and London was followed by "permanent" consultant appointments in Bristol, with a year as retina fellow at the Massachusetts Eye and Ear Infirmary, then London, then chairborne in Manchester and Edinburgh. Many opportunities for advances in ophthalmology were missed, but there were some successes: beta-blockers and steroid blockers in glaucoma, and gene mapping of one X-linked retinitis pigmentosa gene. Hypothesis-making is advocated by regarding no situation as static or sacrosanct, maintaining wide interests and collaborating with basic scientists.

Leber's hereditary optic neuropathy and Kearns-Sayre syndrome: mitochondrial DNA mutations.

Mitochondrial DNA (mt DNA) supplies extranuclear (cytoplasmic) genes which program the manufacture of 13 of the 67 peptides of the mitochondrial respiratory enzymes. The remaining 54 are coded by nuclear DNA. All human children and adults, male and female, are entirely dependent on the cytoplasm of the ovum for their complement of mt DNA; the sperm contributes none. Accordingly, mutations in the mt DNA in a mother's ova will be passed on to all her children, although not all are clinically affected. Leber's hereditary optic neuropathy is in most cases due to a mutation that leads to the replacement of guanine by adenine at position 11778 in mt DNA. This causes histidine to be inserted instead of the normal arginine at the site of the 340th amino acid in the respiratory enzyme NADH subunit 4, hence its defective function. Other point mutations in the mt DNA coding for polypeptides of the respiratory chain complex or controlling sequences coded by mt DNA have been found in other families with Leber's hereditary optic neuropathy. Mitochondrial DNA is the site of other mutations as well. For ophthalmologists, the most important of these is the rare Kearns-Sayre syndrome (pigmentary retinopathy plus muscular dystrophies, especially of the extraocular muscles). Kearns-Sayre syndrome is due to deletions in the mt DNA, which vary in size and so affect a number of different respiratory enzymes, hence the variable manifestations. Cases are usually sporadic because the disease is often so severe that affected individuals do not reproduce if they survive, but in some cases inheritance from the mother has been reported.

Timolol in operated closed-angle glaucoma.

Tonometry in 9 eyes (7 patients) provides some evidence that timolol eye drops are useful in improving control of pressure in eyes operated for closed-angle glaucoma. In cases 1 and 2 (Figs, 1 and 2) this beta 1 and 2 blocker reduced pressure consistently. Case 3 (Fig. 3) showed that timolol 0.5% twice daily was as effective as pilocarpine 2% or 4% with adrenaline 1%. The effect of timolol 0.5% in case 4 (Fig. 4) and case 6 (Fig. 6) was additive to pilocarpine and adrenaline; in case 5 (Fig. 5) it probably improved the effect of adrenaline, but in cases 4 and 5 there may have been some loss of effect with time. Case 7 (Fig. 7) showed a good effect of timolol, reversed on withdrawal, but pressure fell again in spite of continued withholding of timolol. Timolol will be especially valuable in the control of pressure if an operation involving iridectomy has not been completely successful in open-angle glaucoma or more especially in closed-angle glaucoma because it has no effect on the pupil. Miotics will tend to produce posterior pupillary synechiae because aqueous humour will go through the iridectomy, not under the edge of the pupil. The danger will be greater in eyes with closed-angle glaucoma because the pupil is closely applied to the anterior lens surface, which will also tend to produce irritative iridocyclitis.

Ocular hypotensive effect of late pregnancy with and without high blood pressure.

The mean ocular tension of third trimester hypertensive pregnant women did not differ significantly from that of third trimester non-hypertensives, in contrast to the tendency for open-angle glaucoma to be associated with vascular hypertension. Presumably there are different causes for the two types of vascular hypertension. The ocular hypotensive effect of late pregnancy (third trimester) was confirmed.

Lens extraction with ultrasound. Experiments in rabbits.

The extraction of the rabbit lens is described using a 25 G irrigating needle and a 22 G aspirating needle; at the latter's bevelled tip lens fragmentation occurs due to the longitudinal ultrasonic vibrations generated there--an 'acoustic horn' causes the tip to vibrate with large amplitudes. The use of small needles allows considerable manoeuvrability in the anterior chamber and usually eliminates the need for corneal suturing. Push-pull coupled syringes equate the volume of irrigation with that of aspiration. This procedure makes possible lens extraction through an aperture in the anterior capsule of the rabbit's lens and a similar machine is being constructed for trial on human cataract.

Late reoperations for squint.

Ten patients in the age range 2 to 22 years are described who had operations initially for squint in childhood. Nine had had concomitant convergent strabismus and one divergent. All presented again in adult life with a cosmetic complaint, but two also had diplopia. Reoperations were done, age range 14 to 43. These ten were all the "late reoperations" for squint which were done during the four year period 1972 to 1976 by one consultant (C.I.P.). Technically these late reoperations were not difficult, through the amount of change predictable in position of the eyeball could be only approximate. Recession +/- advancement +/- resection of horizontal recti were done in all cases. In one case no medial rectus was identified attached to the eyeball; a mass of tissue behind the caruncle was mobilised and sutured to the globe with resultant good movement. To avoid tethering of the eye by scarred conjunctiva, vertical conjunctival incisions were often converted at suturing to (see article) shaped wounds. The absence of any new cases of diplopia (the two who had it preoperatively retained it without aggravation) is attributed to the fact that all cases were under-corrected, i.e., no convergent or divergent squint was converted into a divergent or convergent squint respectively, so that the non-corresponding image remained within the area of suppression, which probably extends only to the vertical meridian in a squinting eye.

Aqueous humour turnover and intraocular pressure during menstruation.

Both intraocular pressure and aqueous humour turnover rate were determined at intervals over three months in three females in order to investigate whether a correlation existed between these variables and the menstrual cycle. Not only was there a lack of correlation between intraocular pressure or aqueous humour flow rate and menses but intraocular pressure and aqueous humour flow rate were also not related to each other. If pharmacologically administered doses of progesterone or oestrogen influence intraocular pressure, the present data indicate that the effect is probably mediated through effects on the aqueous outflow pathways.

Blindness in schoolchildren: importance of heredity, congenital cataract, and prematurity.

Of 99 children in the Royal Blind School, Edinburgh (which serves Scotland and part of N E England), 15 had optic atrophy (hydrocephalus 4, intracranial haemorrhage 2, prematurity 2, fetal distress 2, birth asphyxia 2, cerebral atrophy 1, cardiac arrest during hernia operation 1, and leukaemia 1). Fourteen had congenital cataract, 12 congenital retinal aplasia (Leber's congenital amaurosis) and 11 retinopathy of prematurity. There were small numbers in many other diagnostic categories, including three with non-accidental head injury. Mental retardation, spasticity, and nystagmus were frequent other correlates in all diagnostic categories. 'Very probably hereditary' was a conservative attribution in 36, while 'probable' seemed appropriate for 12-that is, almost 48% were hereditary. Only about 11 cases might have been prevented through genetic counselling, which testifies to the frequency of autosomal recessive hereditary disease, although no parents were consanguineous.

Posterior synechiae after glaucoma operations: aggravation by shallow anterior chamber and pilocarpine.

Posterior pupillary synechiae affect a proportion of eyes subjected to iridectomy with or without drainage operation because (1) aqueous humour bypasses the pupil; (2) traumatic iridocyclitis occurs; (3) there is immobility of the iris in the iridectomy sector; (4) in eyes with angle closure glaucoma closer apposition of the iris to the anterior lens capsule increases the tendency; (5) pilocarpine aggravates (4) both in angle closure glaucoma and open angle glaucoma and produces a small immobile pupil facilitating pupillary membrane formation (occlusio pupillae). Pilocarpine should be avoided if possible as medical treatment at any time after a drainage operation. A beta blocker is the drug of choice. To eliminate posterior synechiae over a fair number of degrees of pupil (say 30 degrees) sector iridectomy can be done.

Vicryl (polyglactin 910) in cataract surgery. A controlled trial.

In a controlled, randomized trial in 45 cataract operations a new synthetic absorbable suture (8-0 monofilament Vicryl, made by Ethicon), was compared with monofilament nylon or virgin silk normally used. There was a higher incidence of early complications-hyphaema, shallow anterior chamber, and choroidal detachment (15-4 per cent v. 0 per cent)-with the absorbable suture. But these differences were not significant at the 0-05 level and might well disappear with more operative experience, particularly the modified technique of knot-tying. In handling qualities Vicryl was superior to both 10-0 monofilament nylon and 8-0 virgin silk with the exception of knot-tying, in which it was inferior to 8-0 virgin silk. Vicryl is considered to be a useful absorbable suture in cataract surgery but knot-tying requires modification of technique.

Atenolol versus propranolol. A comparison of ocular hypotensive effect of an oral dose.

In a controlled double-blind cross-over trial in 10 patients comprising six with open-angle glaucoma, three with closed-angle glaucoma, and one with ocular hypertension, a single oral dose of atenolol (50 mg) was significantly more effective than propranolol (40 mg) in reducing ocular tension.

Ocular hypotensive effect of atenolol (Tenormin, I.C.I.). A new beta-adrenergic blocker.

Atenolol (Tenormin or I.C.I. 66082) is a new beta-adrenergic blocking drug, unique in being cardio-selective and in having no intrinsic sympathomimetic or membrane activity. In a controlled double-blind study, a single 50 mg oral dose produced a significant fall in ocular tension for about 7 hours in five patients with definite or suspected glaucoma. The average maximum fall was 35 per cent of the initial pressure; it occurred at 5 hours after oral ingestion. Accordingly neither intrinsic sympathomimetic nor membrane activity can account for all the ocular hypotensive effect of beta blockers in humans. The practical implications for treatment of glaucoma require longer-term investigations some of which are in progress.

Atenolol versus adrenaline eye drops and an evaluation of these two combined.

In a 1-day, 1-dose, double-masked, randomised trial, with each of 12 patients acting as his/her own control, atenolol drops 4% (a selective beta1-adrenergic blocker) produced a significantly greater fall in ocular tension measured by applanation than did adrenaline drops 1% (P is less than 0.01 Wilcoxon matched pairs signed ranks test). The mean differences, which favoured atenolol, between the falls in pressure produced by these 2 drugs at 1.5 hours, 3.5 hours, 5.5 hours, and 7 hours after instillation of the drops was 2.1, 4.6, 4.0, and 3.6 mmHg, respectively. Long-term studies would be required before any conclusion was justified about the relative merits of these 2 drugs in the treatment of glaucoma. There was no significant difference between the ocular hypotensive effects of atenolol-then-adrenaline and adrenaline-then-atenolol. It was disappointing that the expected adjuvant effect of atenolol's preceding adrenaline was not found-rather the reverse. Atenolol alone, however, was significantly better than atenolol-then-adrenaline (P is less than 0.02 Wilcoxon matched pairs signed ranks test), and there was also some indication that it was superior to adrenaline-then-atenolol. The response to adrenaline did not differ markedly from the response to the combination in either order.

Subconjunctival suspension of RU486 lowers intraocular pressure in normal rabbits.

RU486 is both a progesterone blocker and a corticosteroid blocker (peripheral). Subconjunctival injections of 0.2 ml of a 1% suspension of RU486 powder (2 mg) were given twice weekly to one eye chosen at random of 12 rabbits. The fellow eye received the same volume, 0.2 ml, of vehicle (normal saline) only. Ocular tension was measured twice daily for six days per week by an Alcon pneumatonograph, the tonometrist(s) being unaware of which eyes were treated and which untreated. A small but significant reduction in intraocular pressure, about 0.7 mmHg, occurred in treated eyes. No intereye difference in the ocular hypertensive response to intraperitoneal injections of distilled water (50 ml/kg) was found. Clinical trials are planned in which a larger fall is expected because the trabecular meshwork in patients with open-angle glaucoma or ocular hypertension is presumably more affected by (normal) tissue levels of corticosteroid.

Penetration of timolol eye drops into human aqueous humour: the first hour.

Samples of aqueous humour were removed from 26 eyes at the start of cataract extraction. Two drops of timolol 0.5% had been instilled into the conjunctival sac 12-71 minutes before operation. Analysis by gas chromatography showed a mean timolol concentration of 55.46 ng/mg, with a range of 8 to 100 ng/mg.

Some blood plasma constituents correlate with human cataract.

AIMS: To look for differences between matched pairs of patients and controls in concentrations of various plasma constituents which might indicate dysfunctions associated with cataract. METHOD: One thousand patients were taken from the cataract waiting list of a specialist eye hospital. For each patient a matched control of the same sex and half-decade of age but without cataract was taken from the patient list of the family doctor of the patient; the control was the next alphabetically after the patient on the doctor's list. The patients and controls were visited in their homes by a team of nurses who performed venepunctures and collected information for a questionnaire. Eye examinations were performed by a team of ophthalmologists. RESULTS: Significant differences were found between the cataract and control groups in 10 of the 18 examined plasma constituents. A constellation of three--bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase--was significantly higher in the cataract group, suggesting subclinical liver dysfunction as a risk factor. Steroid treatment and diabetes increased cataract risk. Endogenous basal plasma cortisol levels were raised in the cataract group, irrespective of steroid use and diabetic status. Alkaline phosphatase, calcium, glucose, and sodium were all raised in the cataract group. Given the raised total protein and albumin also found in the cataract group, the lower albumin/(total protein-albumin) ratio (an approximation for albumin/globulin ratio) may imply an increase in globulin, suggestive of possible (chronic) infection. Total cholesterol was lower in the cataract group. CONCLUSION: Human cataract in older age groups seems to be due to an accumulation of risk factors, even if individual mean concentrations are well within normal limits but, of course, differing significantly from the corresponding means in the control population.

Comparison of ocular hypotensive effects of acetazolamide and atenolol.

The ocular hypotensive effect of single oral doses of (a) atenolol (50 mg), (b) acetazolamide (500 mg), (c) atenolol (50 mg) and acetazolamide (500 mg) in combination, and (d) vehicle (inert tablets) were compared in 8 patients with glaucoma. In this single-dose, double-masked trial the combination was observed as most effective in reducing ocular tension. Both the combination and atenolol performed markedly better than vehicle. That acetazolamide did not reduce ocular tension significantly more than vehicle is probably explained by relatively low initial ocular tensions. There was no evidence of interaction between atenolol and acetazolamide in this study. Acetazolamide probably remains the first-choice oral medication for glaucoma. It is cautiously suggested that beta-blocking drugs may have a future therapeutic role, but longer-term studies on larger numbers will be required to establish this.

Atenolol eye drops in glaucoma: a double-masked, controlled study.

Guttae atenolol 4% (Tenormin), a pure beta1-blocking (i.e., cardioselective) drug, produced a median overall fall of 5-6 mmHg (range 3-2 to 13-2 mmHg) in the first tonometrised eyes of 7 patients with open-angle glaucoma or ocular hypertension and 1 with closed-angle glaucoma (off any treatment for the whole of the day preceding each test day) after allowance for an 'effect' of guttae saline 0-9%, in a double-masked, cross-over trial. By a Wilcoxon matched pairs rank test this was significant at the P less than 0-05 level. The median overall fall of 3-5 mmHg (range 0-8 to 10-8 mmHg) in the second-tonometrised eyes of 7 patients (1 of the 8 contributed only 1 eye) was also significant (P less than 0-05). In 2 patients who had been treated with guttae atenolol 4% daily 3 X for 1 and 2 months there is evidence that, on replacing the atenolol 4% with saline 0-9%, a rise of pressure of around 3 mmHg occurred 2 and 3 and 5 days later, i.e., the drug still retained its effectivity (slightly reduced) after 1 and 2 months.

Probably Norrie's disease due to mutation. Two sporadic sibships of two males each, a necropsy of one case, and, given Norrie's disease, a calculation of the gene mutation frequency.

Two sibships, each with two affected males but no other affected family members, are described. All four patients at birth had small eyes with white masses visible behind clear lenses. Support for a diagnosis of Norrie's disease lies in the probable mental retardation and sudden death of one child and mental retardation in the other in one of the families, and strong support in the sensorineural deafness in one child in the other family. A necropsy was performed on the dead child. Both eyes showed the retinae to be totally non-attached. The optic nerves were thin. If the diagnosis is Norrie's disease (highly probable), the birth of the second affected child in each family supports the postulate of a mutation in the X chromosome of a germ cell of a maternal grandparent or an earlier maternal ancestor, no previous member of the family having been affected. That implies a 50% risk of the disease in future male siblings and a 50% risk of the carrier state in female sibs. When only one child is affected, the explanation could also be a mutation in that individual. Given Norrie's disease, we have calculated a mutation rate of 3.9 per million chromosomes in the Scottish population--remarkably similar to the mutation rates calculated for many dominant diseases. A diagnosis of autosomal recessive non-attachment of retina implies a 25% risk to later siblings.