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Purpose: The aims of the present research were to determine (a) the age at which children with typical development understand the concept of opposite, (b) whether this is related to other cognitive abilities or experiences, and (c) whether there is early implicit understanding of the concept., Method: Children (N = 204) between 3 and 5 years of age were randomly assigned to 1 of 3 experimental conditions in a novel opposite task. Children's language and working memory skills were assessed, and parents provided information about children's access to learning materials about opposites., Results: In the opposite task, 4- and 5-year-olds, but not 3-year-olds, demonstrated acquisition of the concept of opposite. Children demonstrated this understanding only when asked for the "opposite" one, suggesting that antonymy was not made salient by stimulus properties alone. Children's accuracy was not significantly related to their language or working memory skills, to their child care experience, or to whether parents reported having books or games about opposites or playing opposite word games with children. Eye gaze analyses provided no evidence for early implicit understanding of the concept of opposite., Conclusion: Children with typical development have a concept of opposite by 4 years of age.

The newly excysted juvenile (NEJ) stage of the Fasciola hepatica lifecycle occurs just prior to invasion into the wall of the gut of the host, rendering it an important target for drug development. The cathepsin B enzymes from NEJ flukes have recently been demonstrated to be crucial to invasion and migration by the parasite. Here we characterize one of the cathepsin B enzymes (recombinant FhcatB1) from NEJ flukes. FhcatB1 has biochemical properties distinct from mammalian cathepsin B enzymes, with an atypical preference for Ile over Leu or Arg residues at the P(2) substrate position and an inability to act as an exopeptidase. FhcatB1 was active across a broad pH range (optimal activity at pH 5.5-7.0) and resistant to inhibition by cystatin family inhibitors from sheep and humans, suggesting that this enzyme would be able to function in extracellular environments in its mammalian hosts. It appears, however, that the FhcatB1 protease functions largely as a digestive enzyme in the gut of the parasite, due to the localization of a specific, fluorescently labeled inhibitor with an Ile at the P(2) position. Molecular modelling and dynamics were used to predict the basis for the unusual substrate specificity: a P(2) Ile residue positions the substrate optimally for interaction with catalytic residues of the enzyme, and the enzyme lacks an occluding loop His residue crucial for exopeptidase activity. The unique features of the enzyme, particularly with regard to its specificity and likely importance to a vital stage of the parasite's life cycle, make it an excellent target for therapeutic inhibitors or vaccination.

The medial frontal cortex (MFC) is involved in the temporal organization of behaviour. It receives timing information from the master circadian clock in the suprachiasmatic nucleus (SCN), and exhibits daily oscillations in gene expression itself. In this study, we evaluate various properties of circadian rhythms of locomotor activity following neonatal or adult MFC aspiration lesions. Mice with neonatal lesions were more active during the day than mice with adult lesions and less active during the early night than both mice with adult lesions and control mice. Compared to controls, mice with neonatal lesions exhibited smaller phase delays to an early-night light pulse and marginally larger phase advances to a late-night light pulse. Mice with adult lesions did not differ from controls on either measure. The results suggest that the timing of behaviour is determined by an interaction between the MFC and the SCN and that injury early in life has a significant effect on the ability of animals to organize such behaviours., ((c) 2009 S. Karger AG, Basel.)

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.

Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells.

The availability of complete genome sequences for a large number of pathogenic organisms has opened the door for large-scale proteomic studies to dissect both protein expression/regulation and function. This review highlights key proteomic methods including two-dimensional gel electrophoresis, reference mapping, protein expression profiling and recent advances in gel-free separation techniques that have made a significant impact on the resolution of complex proteomes. In addition, we highlight recent developments in the field of chemical proteomics, a branch of proteomics aimed at functionally profiling a proteome. These techniques include the development of activity-based probes and activity-based protein profiling methods as well as the use of synthetic small molecule libraries to screen for pharmacological tools to perturb basic biological processes. This review will focus on the applications of these technologies to the field of microbiology.

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.

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.

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.

European Starlings (Sturnus vulgaris) are often pests in commercial fruit crops in North America and Europe. Because starlings slack the digestive enzyme sucrase and cannot digest sucrose, they may develop an aversion to high-sucrose fruits. In water-tube drinking trials, we tested captive starlings with aqueous solutions of 15% (mass/volume) mixed sugars to identify the level of sucrose required to develop a conditioned feeding aversion when digestible sugars are present. In one-tube tests, starlings decreased intake of 11.25 and 15% sucrose solutions relative to their pretest intake of a 15% glucose-fructose mixture. In two-tube tests with sucrose solutions paired against a digestible glucose-fructose solution, starlings decreased preferences for the sucrose solutions as sucrose concentrations increased. These data suggest that the presence of digestible nutrients mitigates the effect of sucrose in sucrase-deficient birds and that a fruit cultivar would require @> 11.25% sucrose to repel starlings., (© 1993 by the Ecological Society of America.)

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.

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.

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 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.

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.

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.

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.

Sporadic reports describing cases of corneal deformation (i.e. corneal warpage with astigmatism or keratoconus) after a minimum of about 4 years contact lens wear are condensed into Table 1. Some severe cases required corneal grafting. Eight personal cases are described in Table 2, including two who have worn only soft lenses and one who has worn soft lenses for 6 out of 7 years. It is suggested that although some cases of this corneal distortion might well have occurred without contact lenses, the trauma of years of contact lens wear is causative if the individual's cornea is predisposed, possibly by the carrier state of hereditary naturally-occurring keratoconus. A risk-averse patient and practitioner would probably add this to other possible complications, and restrict contact lenses to eyes with more severe refractive errors, and minimise the wearing time.

The frequency and density of corneal arcus in 101 patients (101 eyes), 54 males and 47 females, were greatest in the 12 o'clock sector of the peripheral cornea. Sectors below 12, nasally and temporally, were approximately symmetrically affected. Both properties decreased progressively and significantly at the 11 and 1 o'clock sectors, then 10/2, then 9/3; 8/4 and 7/5 differed insignificantly from each other but were significantly less affected than 9/3, and more affected than 6 o'clock. Breadth and density were significantly positively correlated. The greater vascularity and higher temperature at the upper limbus might explain this pattern. The morphology of arcus is concluded to indicate the site of a peripheral corneal filter which prevents ingress of large light-scattering particles with the centripetal flow of tissue fluid. Filtration of immune complexes at the same site may initiate tissue destruction, hence some peripheral corneal ulcerations.

Topical dexamethasone was used to elevate rabbit intraocular pressure in order to study the interaction with a steroid antagonist, mifepristone. Dexamethasone did not cause a consistently significant increase in intraocular pressure. Animals treated with mifepristone followed by dexamethasone showed no apparent increase in intraocular pressure after dexamethasone, indeed mifepristone caused a lower intraocular pressure than seen in other groups whether in the presence or absence of dexamethasone. Reductions of intraocular pressure when mifepristone was given after 14 days of dexamethasone administration were not found. No conclusion can be reached regarding any dexamethasone antagonism by mifepristone, except that intraocular pressure tended to be lower even in the presence of dexamethasone.

The interaction between a topically administered progesterone, medrysone, and a steroid antagonist, mifepristone, on rabbit intraocular pressure (IOP) has been determined. Medrysone alone increased IOP significantly above parallel controls over the first three weeks; this increase was not sustained. When medrysone and mifepristone were given simultaneously the IOP increased initially, but then fell after two weeks to control levels. When mifepristone was added 14 days after medrysone, the IOP was again reduced to, or below, control levels by mifepristone. The use of mifepristone alone reduced IOP relative to controls and the further addition of medrysone at 14 days had no effect on IOP. It appears that mifepristone is an effective antagonist against progesterone effects on IOP.

A 60-year-old man had variable visual acuity especially in the right eye for 2 years. The right field of vision showed a hemianopic defect on the nasal side (in addition to reduced visual acuity which was due to nuclear cataract). A localized posterior cortical cataract on the temporal side of the right lens accounted for the nasal field defect since the defect disappeared almost completely on dilatation of the pupil, and completely after cataract extraction. Asymmetrical opacities in the optical media far enough anterior or posterior to the plane of the pupil will produce asymmetrical field defects. (An opacity close to the plane of the pupil will produce concentric constriction.)

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.

An ultrasonic lens-disintegrations system is added to the aspiration side of an irrigation-aspiration system. It incorporates an acoustic horn of which one part is a stainless steel cone 4 cm long with a 1 cm diameter base. From the apex of the cone projects the other part, viz. a 22 gauge needle, which is inserted into the anterior chamber at the limbus temporally (left eye) and which carries aspirated lens fragments with saline out into a duct drilled 2 cm into the cone along its axis. At that point the duct turns at right-angles to leave the cone; a polythene tube connects the duct with the aspiration syringe. A vibration generator (sandwich transducer) initiates ultrasonic vibrations which the needle-cone combination magnifies about 100-fold at the tip of the needle. Saline input to and output from the anterior chamber are maintained exactly equal (and simultaneous) by means of a 'push-pull' system of twin reciprocating hand-driven 30 ml. syringes (Fig. 7). Saline input is through a 25 gauge needle at the limbus at 6 o'clock (left eye).

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.

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.

A series of 21 patients with herpetic corneal ulcers was treated by photodynamic inactivation (using a single application of neutral red 1 per cent solution followed by a 15-min exposure to a 40 watt light of 440--550 nm), carbolization, or idoxuridine (IDU) ointment. No significant difference was found in the number that healed, the mean healing time, or the number of recurrences after any of the three treatments.