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.

Influence of dehydroepiandrosterone on rabbit intraocular pressure.

PURPOSE: The systemic concentration of dehydroepiandrosterone decreases with age in primates while in humans intraocular pressure (IOP) increases with aging. This study was designed to investigate if a relationship existed between dehydroepiandrosterone and IOP in pigmented rabbits. METHODS: Animals were treated unilaterally for 6 weeks with topical 3% dehydroepiandrosterone in 30% 2-hydroxypropyl-beta-cyclodextrin; the contralateral eye received vehicle alone. Drops were applied, and IOP measured, twice daily. RESULTS: Small, but statistically significant, drug-related effects were found. IOP was consistently higher in the afternoon; the afternoon minus morning difference in IOP, however, decreased with time. Topical, radioactive drug application indicated very low level penetration into aqueous humor, iris, corneal epithelium, the rest of the cornea, or bulbar conjunctiva. CONCLUSION: The small drug-related effects may be due, in large part, to poor intraocular drug penetration. The circadian rhythm of IOP appears to be time-dependent in chronic studies with a gradual loss of IOP difference between a.m. and p.m. readings.

Some plasma constituents correlate with human cataract location and nuclear colour.

AIMS: To look for differences in levels of various plasma constituents between pair-matched controls and patients who had cataracts classified by location and appearance of lens opacity and nuclear colour in order to identify systemic risk factors. METHODS: 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. At an early morning visit to the homes of both patients and controls, fasting, a team of nurses performed venepunctures and collected information for a questionnaire. Eye examinations were performed by a team of ophthalmologists. RESULTS: Predominantly nuclear cataract was significantly associated with raised plasma alanine aminotransferase and bilirubin, posterior subcapsular cataract with increased calcium and urea, cuneiform with reduced potassium, mature/hypermature with raised potassium and reduced total carbon dioxide. The following were consistently significantly associated with all forms of cataract; diabetes and raised plasma glucose (not in non-diabetics), use of steroid medication, raised levels of cortisol (steroid users excluded), albumin, alkaline phosphatase, gamma-glutamyl transpeptidase, sodium and total protein and reduced levels of cholesterol and albumin/(total protein-albumin) ratio (an approximation for the albumin/globulin ratio). The multivariate analysis indicated that the most important non-specific cataractogenic effects were those of increased total protein, diabetes and use of steroid medication. CONCLUSION: This and other studies support, broadly, the conclusions that senile or age-related cataract is not merely caused by increasing age and also that various morphological types have different risk factors. The mechanisms underlying the biochemical associations with different patterns of lens opacification and the identification of the ultimate risk factors remain to be elucidated.

Skin disease and age-related cataract.

Dermatological conditions and treatments were analysed in a study comparing cataract patients and stringently matched controls. One thousand patients were taken from the cataract waiting list of a specialist eye hospital. For each patient a matched control of the same gender, half-decade of age, and family doctor but without cataract was selected. Venepunctures and eye examinations were performed on both patients and controls; in addition, questionnaire information was obtained from each. Age-related cataract is significantly associated with dermatological abnormality and its treatment, the former association being more significant and more pronounced after 69 years of age. The association of hydrocortisone use after 69 years of age and cataract, however, remains significant even after adjustments for dermatological abnormality and steroid use, suggesting that even among steroid medications hydrocortisone is particularly strongly associated with cataract.

Human cataract risk factors: significance of abstention from, and high consumption of, ethanol (U-curve) and non-significance of smoking.

Current ethanol consumption and cigarette smoking were quantified by questionnaire in Edinburgh and suburbs, Scotland, UK. Stringently matched cataract-control pairs (n = 990 and 858, respectively) were included. For ethanol, 'light and infrequent' consumption and 'light and frequent' were associated with a significantly lower risk of cataract than were total abstention and 'occasional' consumption; the prevalence of cataract rose with further increases in consumption, suggesting a U-shaped curve. For nuclear cataract, white in particular, there is a significant trend with amount consumed. Smoking was not found to be a risk factor.

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.

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.

Granny knot for interrupted 10-0 nylon sutures in cataract sections.

A granny knot instead of a reef (square) knot is advocated for 10-0 nylon interrupted sutures in limbal cataract sections, especially under a conjunctival flap. The second of the two throws is looped in the direction opposite to that in a reef knot so that the free ends lie at right angles to the plane of the suture. The second throw is used to "run down" the first to tighten the suture. To avoid postoperative erosion through conjunctiva, the ends are cut long with a blade while they lie flush with the sclera. The knot is locked when the traction required to tighten the suture is released and the thinned nylon recovers its original diameter on each side of the knot.

Saucerisation (recession) of neuro-retinal rim is characteristic of glaucoma.

Colour stereophotographs of the optic disc and surrounding retina were assessed by a Humphrey analyser system in a series of Japanese individuals. When compared with 9 age- and sex-matched control eyes (9 controls), the 10 eyes of 10 patients with early open-angle glaucoma showed a significantly lower level of the mid-point of the neuroretinal rim relative to the level of the surface of the retina about 1/4 of a disc diameter beyond the disc edge. When the mid-point of the rim was related to the surface of tissue at the disc edge, the level of the former was significantly lower at the three measurement points on the nasal side and at 6 o'clock. In the 9 normal controls, the lower half of the neuro-retinal rim was at a significantly lower level than the upper half, relative to the surface of tissue at the disc edge. We conclude that saucerisation and/or recession of the neuro-retinal rim frequently accompanies glaucoma and we suspect it is an early sign of it.

Autosomal recessive 'optic atrophy' with late onset and evidence of ganglion cell dysfunction: a sibship of two females.

Two sisters aged about 40 years presented with a recent moderate reduction in visual acuity and pale optic discs. The nonconsanguineous parents, 7 other siblings and all other family members have normal vision. This strongly indicates a hereditary, autosomal recessive origin. A primary ganglion cell pathology is strongly suspected because of the significant attenuation of the early component of the onset/offset visual-evoked potential in the presence of little change in the potential to a pattern reversal stimulus.

Ocular pulsation correlates with ocular tension: the choroid as piston for an aqueous pump?

In 26 random out-patients, including 13 treated glaucoma patients and ocular hypertensives, the higher the ocular tension, the greater the pulse amplitude, by Alcon pneumotonometry, at a statistically significant level. In a single untreated hypertensive, when 2-hourly pneumotonometry was done for 24 h, the correlation was similar and significant. The higher the diastolic blood pressure, the higher the ocular pulsation, also significantly. Pulsation is suggested to be a pump, the choroid being the piston, contributing (1) to an increase in the outflow of aqueous humour and (2) to a homeostatic mechanism contributing to normalization of the intra-ocular pressure, wherein pulsation increases or decreases, as the intraocular pressure increases or decreases, respectively.

Rabbit diurnal ocular tension variations.

Ocular tension recorded by pneumatonography was estimated at 4-hour intervals during six consecutive 24-hour periods in 8 New Zealand rabbits. The animals had been acclimatized for more than 8 weeks to artificial light from 08.00 to 20.00 h and dark for the other 12 h. Inter- and intrarabbit consistency was enough to allow the generalization that the lowest pressure occurred at noon (mean -0.8 mm Hg from baseline average), while the highest pressures (mean + 1.2 mm Hg above baseline average) occurred at 16.00 and 20.00 h. Only three other studies have measured rabbit ocular tensions throughout 24 h, but for shorter periods: one observed a light-induced rise as in the present study, but the other two studies found a rise during darkness.

Congenital alacrima without associated manifestations (AD). An affected father and son.

The authors report a Kuwaiti Arab family in which the father and one of his two sons have severe hypolacrimation with blotchy staining of the cornea and punctate staining of the interpalpebral bulbar conjunctiva by fluorescein and Rose Bengal. Pharmacologic testing together with biochemical analysis and systemic examinations and investigations suggest an isolated dysfunction of lacrimation. The authors' small Arab family differs from the only other recorded pedigree (Irish) in which all five affected members in four generations also had atopy.

Central pulverulent (Coppock) cataracts. A sibship of two Arab females with full-cousin normal parents.

Two Arab (Saudi) sisters are described each with bilateral typical central pulverulent (powdery) or Coppock cataracts. As their unaffected parents are first cousins, the heredity is probably autosomal recessive, unlike the autosomal dominant heredity of the vast majority of previously described cases in the literature. Chromosomes were normal in all four individuals. There are no other children in the family. Both children and both parents were phenotypically Fy a - b+, reasonably common in Arab populations, so that any linkage to the Duffy blood group is neither supported nor refuted.

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.