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BACKGROUND: Impairment in initiating joint attention (IJA) is associated with autism spectrum disorder (ASD) in children, although it is unclear when impairments arise. Due to the early development of IJA use and late diagnosis of ASD, groups at high-risk of ASD, such as infants with an older sibling with ASD (ASIBs) and infants with fragile X syndrome (FXS), provide opportunities to study early IJA behaviours for children who are later diagnosed with ASD. This study analysed these two groups to determine if IJA use differed compared to typically developing (TD) peers at 12 months and whether IJA was associated with later ASD outcomes. METHOD: An experimental attention task was used to analyse IJA gaze shifts and gestures in the high-risk groups. Clinical best estimate diagnoses were given to each participant to compare IJA behaviours to ASD severity. RESULTS: No differences in the frequency of IJA gaze shifts and gestures were found between 12-month-old ASIBs and TD controls, but infants with FXS demonstrated a significantly reduced range of IJA gaze shifts relative to TD controls. Additionally, ASD outcomes at 24 months were related to IJA use for infants with FXS at 12 months, but not infant ASIBs, though these findings were explained by differences in nonverbal cognitive development. CONCLUSIONS: Although previous studies have reported delays in IJA use in children with FXS and ASIBs at ages 21 and 14 months, respectively, our results suggest IJA behaviours for these high-risk groups are not distinct from TD children at 12 months. When differences were found at 12 months, they were explained by nonverbal cognitive development, particularly for infants with FXS. Differences in IJA use at 12 months in this study were too small to serve as a potential indicator of later ASD.

The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort.Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time.Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later.In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement.

This article is concerned with a numerical model for flow in a porous medium containing fractures. The fractures are modeled as (d − 1)-dimensional surfaces inside the d-dimensional matrix domain, and a mixed finite element method containing both d and (d − 1) dimensional elements is used. The method allows for fluid exchange between the fractures and the matrix. The method is defined for single-phase Darcy flow throughout the domain and for Forchheimer flow in the fractures. We also consider the case of two-phase flow in a domain in which the fractures and the matrix are of different rock type.

Although it is widely accepted that to resolve the ‘horizon’ problem the early Universe must have undergone a sudden expansion (cosmic inflation), what mechanism drove this process is less clear. In the braneworld scenario, it is suggested that inflationary epochs may have been initiated and terminated by brane collisions and annihilations1,2,3. Branes are objects of lower dimensionality embedded in a higher-dimensional matrix. For example, we may live on a three-dimensional brane embedded in a four-dimensional matrix. However, such structures are so far removed from everyday reality that bringing physical insight to bear is difficult. Here we report laboratory experiments where we simulate brane annihilation using the closest brane analogue to which we have access, the coherent phase boundary between the two phases of superfluid 3He. When two branes collide or annihilate, topological defects may be created, whose influence may still be detectable today. By creating a brane–antibrane pair in superfluid 3He and subsequently annihilating it, we can detect that defects are indeed created in the superfluid texture (the superfluid analogue of spacetime), thus confirming that the concept of defect formation after brane annihilation in the early Universe can be reproduced in analogous systems in the laboratory.

We present measurements of the response of the B-like phase of superfluid 3He in aerogel to an applied flow. The measurements are made using a cylindrical piece of 98% silica aerogel attached to a vibrating wire resonator. The resonator is immersed in superfluid 3He at 16 bar pressure and at low temperatures. A variable magnetic field is applied such that the aerogel-confined superfluid may exist in the A-like or B-like phase, while the surrounding fluid is always in the bulk B-phase. The resonator response reveals a velocity dependence of the inferred aerogel-confined superfluid fraction. We discuss measurements of the temperature and magnetic field dependence of the response in the B-like phase. We find a significant field dependence indicating a strong magnetic distortion of the B-like phase order parameter.

We present measurements of the response of the A-like phase of superfluid 3He in aerogel to an applied flow. The measurements are made using a cylindrical piece of 98% silica aerogel attached to a vibrating wire resonator. The resonator is immersed in superfluid 3He at low temperatures and relatively high magnetic fields such that the aerogel confined superfluid is in the A-like phase, while the surrounding fluid is in the bulk B-phase. We observe a variety of interesting non-linear and hysteretic effects when the resonator is driven to higher velocities. We present some of our preliminary findings and speculate on their implications.

We present measurements of the transport of superfluid 3He quasiparticle excitations in the ballistic limit at temperatures well below Tc, and an interpretation of unexpected results as an experimental simulation of cosmological processes. Using a variable magnetic field profile we stabilize a layer of A phase across a cylinder of B phase, creating both an AB and a BA interface. These highly ordered interfaces may provide an ideal laboratory analogy for the branes and anti-branes of current cosmology. It has been suggested that brane interaction and annihilation are involved in inflation in the early Universe and leave behind topological defects such as cosmic strings. In our experiments we have annihilated our AB/BA branes by ramping down the magnetic field to remove the A phase layer. We then find that the quasiparticles face an extra impedance owing to defects left behind in the B phase texture. This is the first definitive observation of such a phenomenon.

Turbulence in classical fluids has far-reaching technological implications but is poorly understood. A better understanding might be gained from studying turbulence in quantum systems. In a pure superfluid (at low temperatures), there is no viscosity and vortex lines are quantised. Quantum turbulence consists of a tangle of quantised vortex lines which interact via their self-induced flow. We have recently developed techniques for detecting vortices in superfluid 3He–B in the low temperature limit. We find that the transition to turbulence from a moving grid occurs by the entanglement of emitted vortex rings. Here, we discuss the propagation of the ballistic vortex rings emitted at low grid velocities. We have measured the temperature at which the rings decay before reaching the detectors. Our results, at two different pressures, confirm that the vortex rings decay in accordance with mutual friction.

We present seeing-limited and adaptive optics (AO) images of the z = 1.786 radio galaxy 3C294 in the H and K' infrared bands obtained at Keck Observatory. The infrared emission of 3C294 is dominated by two distinct components separated by ~1" (9 kpc). The eastern knot contains an unresolved core that contributes ~4% of the K'-band light; we identify this core with the active nucleus. The western component is about 2.5 times brighter. The most plausible interpretation of the near-infrared morphology is an ongoing merger event, with the active nucleus located in the less massive of the two galaxies., Accepted for Publication in Astrophysical Journal

Rescue excavations on an extensive cropmark site at the confluence of the Lyne Water and Meldon Burn in the 1970s revealed several episodes of activity. A limited Mesolithic presence is indicated by the stone finds, but more intensive use is attested from the early/mid fourth millennium BC. Widely scattered groups of pits contained Impressed Ware of the local style. Radiocarbon dates chart this activity down to the early/mid third millennium BC, when a massive timber wall, 600 m long and up to 4 m in height, was constructed to shut off the 8 ha promontory between the Lyne Water and Meldon Burn. A timber avenue led into the enclosure on the north-west; standing posts and stones and settings of posts and stakes were erected; and cremation burials took place in the interior. No cultural material can certainly be associated with this phase and it probably lasted a century or less. A large stockade within the main enclosure could not be dated with certainty. A disturbed cist burial, yielding a jet pendant, 'slug' knife and possible Food Vessel sherds, may have been interred as one ofthe final acts in this phase. Renewed activity came in the mid/late second millennium BC, when the site was used for an extensive cremation cemetery. This involved erecting rows of posts, some standing in pits containing cremations. There was also a burial in a rough cist, and two cremations deposited in Cordoned Urns. There is no evidence for further activity until the Roman period when the road from Newstead to Castledykes was driven through the site, disturbing some of the prehistoric features. There were Roman forts just to the west at Easter Happrew and Lyne, and large temporary camps at Meldon Bridge itself. One of these partly overlay the prehistoric site, and appeared to have been constructed after the road. Long afterwards an 18th-century turnpike road was laid down on top of the old Roman road. At least some of the gravel pits found on both sides of the road were dug in this phase.

Planktonic larval dispersal and recruitment can be major determinants of the structure and dynamics of marine communities. However, these processes have been difficult to study because of their natural variability and the limitations of methods used to collect and analyze plankton samples. In particular, the use of microscopy to determine the composition of plankton samples is time-consuming and often limited by a lack of reliable morphological characters for species identification. The need for methods of greater accuracy and efficiency has led to the development of molecular approaches to plankton analysis, including detection by DNA hybridization, amplification of DNA from plankton samples by the polymerase chain reaction (PCR) and taxonomic characterization by ribosomal DNA sequence analysis. Here we describe a PCR-based method that detects larval crabs in estuarine plankton samples. This technique is unusually expedient and relatively cost-effective. It is based on the detection of a middle repetitive sequence characteristic of the stone crab Menippe mercenaria, as well as the closely related species M. adina. Amplification by PCR of a 585 base pair region of this sequence from plankton samples accurately indicates the presence of either species. Because of the high abundance of this sequence in the genome of Menippe, single larvae can be detected in typical plankton samples. Unlike methods based on 'universal' sequences (rRNA or regions of the mitochondrial genome), the amplification of a PCR product of the expected size is a reliable indication of the presence of the target species, and no further characterization is necessary. This technique is intended to facilitate the large-scale processing of plankton samples that is necessary for accurate determination of the temporal and spatial distributions of individual species in plankton communities.

We are concerned with the problem of computing electromagnetic guided waves in a closed, inhomogeneous, cylindrical wave guide. These waves correspond to solutions of an eigenvalue problem, and classical methods produce, in addition to approximations to the solutions, spurious modes which are particularly troublesome because they correspond to nonzero approximations of the 0 eigenvalue. A nonconforming finite element method for the calculation of guided waves without spurious modes is introduced and analyzed.

Variability in behaviour displayed by children with fragile X syndrome (FXS) may be partially attributable to environmental factors such as maternal responsivity. The purpose of this study was to explore variables associated with maternal behaviour during a task designed to elicit frustration in their children with FXS.Forty-six mother-child dyads, in which the child had full-mutation FXS, were observed in their homes during a task designed to elicit frustration in the child. Each child was given a wrong set of keys and asked to open a box to retrieve a desired toy. Mothers were provided with the correct set of keys and instructed to intervene when they perceived their child was getting too frustrated. Child-expressed frustration and requests for help and maternal behaviours (comforting, negative control, and encouraging/directing) were observed and coded. Maternal variables (e.g. depression, stress, education levels), child variables (e.g. autistic behaviours, age, medication use) and child behaviours (frustration, requests for help) were explored as predictors of maternal behaviour.Almost all mothers intervened to help their children and most used encouraging/directing behaviours, whereas very few used comforting or negative control. Child age and child behaviours during the frustrating event were significant predictors of encouraging/directing behaviours in the mothers. Children whose mothers reported higher depressive symptomology used fewer requests for help, and mothers of children with more autistic behaviours used more negative control.The results of this study suggest that child age and immediate behaviours are more strongly related to maternal responsivity than maternal traits such as depression and stress.

Our main result is that a “restricted Poincaré duality” property with respect to finite dimensional coefficient modules over a field holds for a certain class of groups which includes all soluble groups of finite Hirsch length. This relies on a generalisation to the given class of a module construction by Stammbach; an extension of his result on homological dimension to these groups is given. We also generalise the well-known result that torsion-free soluble groups of finite rank are countable.

Patients with adult periodontitis (AP) exhibit elevated serum antibody levels to Porphyromonas (Bacteroides) gingivalis; however, it is not known whether these antibodies originate from plasma cells in the local disease site or from peripheral lymphoid tissues. We studied the isotype and subclass levels and origin of antibodies to P. gingivalis fimbriae, since elevated serum anti-fimbriae responses were seen when compared with sera of healthy controls. IgG anti-fibriae titres were dominant and the subclass response was IgG3 much greater than IgG1 greater than IgG2 much greater than IgG4; however, some IgA anti-fimbriae antibodies were also seen. The IgA subclass fimbriae-specific response was mainly IgA1; however, significant IgA2 anti-fimbrae antibodies were seen. We also assessed numbers of anti-fimbriae antibody producing cells from peripheral blood mononuclear cells (PMBC) and from either healthy or inflamed gingiva of AP subjects. Gingival mononuclear cells (GMC) of AP patients exhibited high numbers of immunoglobulin-producing (spot-forming) cells (SFC) including fimbriae-specific antibody secreting cells in a pattern of IgG greater than IgA greater than greater than greater than IgM. However, low numbers of SFC were seen in GMC from healthy gingiva; further, no anti-fimbriae SFC responses were noted in healthy GMC. Although no fimbriae-specific immunoglobulin-producing cells were seen in PBMC, low numbers of antigen-specific SFC were found in pokeweed mitogen-triggered PBMC from AP subjects. Treatment of AP patients for plaque and surgical removal of inflamed gingiva resulted in significant reductions in serum anti-fimbriae responses. These studies show that AP patients exhibit brisk serum IgG and IgA subclass anti-fimbriae antibodies, whose origin appear to be the plasma cells present in the localized inflamed tissues.

This study presents measurements of the transport of quasiparticle excitations in the B phase of superfluid 3 He at temperatures below 0.2 T c . We find that creating and then removing a layer of A-phase superfluid leads to a measurable increase in the thermal impedance of the background B phase. This increase must be due to the survival of defects created as the AB and BA interfaces on either side of the A-phase layer annihilate. We speculate that a new type of defect may have been formed. The highly ordered A–B interface may be a good analogy for branes discussed in current cosmology. If so, these experiments may provide insight into how the annihilation of branes can lead to the formation of topological defects such as cosmic strings.

There has been much recent interest in how impurity scattering may affect the phases of the p-wave superfluid He-3. Impurities may be added to the otherwise absolutely pure superfluid by immersing it in aerogel. Some predictions suggest that impurity scattering may destroy orientational order and force all of the superfluid phases to have an isotropic superfluid density. In contrast to this, we present experimental data showing that the response of the A-like phase to superfluid flow is highly anisotropic, revealing a texture that is easily modified by flow.

We have constructed a vertical cylindrical cell in which we cool superfluid 3He to the low temperature limit. At the top and bottom of this cylinder are pairs of vibrating wire resonators (VWRs), one to act as a heater and the other as a thermometer. Quasiparticle excitations are created by driving the heater VWRs. These excitations can only leave the cylinder via a small hole at the top. Using a shaped magnetic field, we can produce a layer of A phase across the tube, while maintaining low field B phase in the vicinity of the VWRs for reliable thermometry. Preliminary results show that the two A‐B interfaces lead to a measurable extra resistance for quasiparticles between the top and bottom of the cylinder.

In the temperature range below 0.2Tc, the gas of thermal excitations from the superfluid 3He‐B ground state is in the ultra‐dilute ballistic regime. Here we discuss preliminary measurements of the transport properties of this quasiparticle gas in a cell of cylindrical geometry with dimensions much smaller than any mean free path. The vertical cylinder, constructed from epoxy‐coated paper, has vibrating wire resonator (VWR) heaters and thermometers at the top and bottom, and a small aperture at the top which provides the only exit for quasiparticles. Using the thermometer VWRs, we measure the difference in quasiparticle density between the top and bottom of the tube when we excite the top or bottom VWR heater. This gives information about the transport of energy along the cylindrical 3He sample and hence about the scattering behaviour involved when a quasiparticle impinges on the cylinder wall.

From our long experience of using profiled magnetic fields to stabilize and manipulate the A-B phase boundary in superfluid He-3, we have constructed a cell in which we can create and move a droplet of B phase, levitated within A phase away from any walls at T similar to 0.15 T-c. Uniquely, the A and B condensates are coherent across the A-B interface and at such low temperatures the superfluid is essentially pure, providing the most ordered phase boundary to which we have laboratory access. We configure the field so that within a bulk volume of superfluid, a region of high field (stabilizing the A phase) completely surrounds a region of lower field (stabilizing the B phase). Our preliminary measurements are at zero pressure and temperatures below 0.3T(c) where the first-order transition from B to A phase is at 340 mT. We observe the formation of the droplet as we ramp the field, and we also study the transport of thermal excitations out of the droplet. Future plans include measurements at higher pressures where the A phase can be stabilized in low magnetic field at temperatures close to T-c. Upon cooling into the B phase we should then be able to make the first studies of nucleation uninfluenced by the presence of container walls.

We give a pedagogical survey of those aspects of the abstract representation theory of quantum groups which are related to the Tannaka-Krein reconstruction problem. We show that every concrete semisimple tensor *-category with conjugates is equivalent to the category of finite dimensional non-degenerate *-representations of a discrete algebraic quantum group. Working in the self-dual framework of algebraic quantum groups, we then relate this to earlier results of S. L. Woronowicz and S. Yamagami. We establish the relation between braidings and R-matrices in this context. Our approach emphasizes the role of the natural transformations of the embedding functor. Thanks to the semisimplicity of our categories and the emphasis on representations rather than corepresentations, our proof is more direct and conceptual than previous reconstructions. As a special case, we reprove the classical Tannaka-Krein result for compact groups. It is only here that analytic aspects enter, otherwise we proceed in a purely algebraic way. In particular, the existence of a Haar functional is reduced to a well known general result concerning discrete multiplier Hopf *-algebras., Latex2e, 43 pages. Uses diagrams.tex V3.88

Hypericin is the ingredient used to standardize the popular over-the-counter antidepressant medication St. John's Wort. Because hypericin readily produces singlet oxygen and other excited state intermediates, it is a very efficient phototoxic agent in the eye that can potentially induce the development of the cataract photooxidative mechanism. Hypericin absorbs in the UV and visible ranges, binds to the lens crystallins (alpha, beta and gamma) and damages these proteins through a photooxidative mechanism. Effects were measured previously using fluorescence, UV and mass spectrometry. We report here two additional methods to monitor lens damage: (1) measuring focal length variability using a ScanTox instrument and (2) measuring protein leakage from the damaged lens. Because nonenzymic glycation results in free radical production, we chose to use elevated glucose concentrations as a convenient model for studying oxidative stress. To compare and contrast photooxidative damage against oxidative damage to the lens, we also measured the focal length variability and protein leakage induced by the presence of elevated glucose concentrations. We found that the total accumulated protein leakage was positively correlated (r = 0.9) with variability in focal length. Lenses treated with hypericin and irradiated with UVB had an increase in focal length variability as compared with the lenses that were only UVB-irradiated. Lenses without UVB irradiation had much lower focal length variability than irradiated lenses. For non-hypericin-treated lenses, UVB-irradiated lenses had a larger variability (4.58 mm) than the unirradiated lenses (1.78 mm). The lenses incubated in elevated glucose concentrations had a focal length variability (3.23 mm) equivalent to that of the unirradiated hypericin-treated lenses (3.54 mm). We conclude that photooxidative damage by hypericin results in changes in the optical properties of the lens, protein leakage and finally cataract formation. In contrast to this, high concentrations of glucose induced protein leakage but not changes in optical properties or the opacity associated with a cataract. This work provides further evidence that people should protect their eyes from intense sunlight when taking St. John's Wort.

A project to upgrade the short-pulse spallation source target at the Los Alamos Neutron Scattering Center (LANSCE) is in progress. This upgrade will reduce the target change out time from about a year to about three weeks and permit the proton beam current to be raised to 200 /spl mu/A. The project includes a new target-moderator-reflector system, a new suite of moderators for four new flight paths, improved auxiliary systems, remote handling capability, and a new crane and service building. The project has also supported calculations and experiments for target neutronics, rod-target thermo-hydraulics, and corrosion-related measurements in a proton beam. The final engineering design is now complete and the project has begun fabrication and procurement. Installation will begin in the fall of this year.

The tryptophan metabolite, xanthurenic acid (Xan), is produced through a transamination reaction in high concentrations in human lenses with age and has been isolated from aged human cataractous lenses. It has appreciable absorption between 300 and 400 nm (lambda max = 334 nm), the range absorbed by the human lens. Our recent studies have shown that unlike most tryptophan metabolites in the eye, Xan is photochemically active, producing both superoxide and singlet oxygen. To determine if Xan could act as a photosensitizer and photooxidize cytosolic lens proteins, alpha-, beta- and gamma-crystallins were irradiated (lambda300 nm, 12 mW/cm2) in the presence and absence of Xan. Upon irradiation and in the presence of Xan, lens proteins polymerized in the order alphabetagamma as assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Further analysis of the photolyzed alpha-crystallin by mass spectrometry indicated that histidine, tryptophan and methionine residues were oxidized at specific positions in a dose-dependent (irradiation time) manner. In alpha A-crystallin two forms of oxidized histidine 154 were observed, 2-imidazolone and 2-oxohistidine. Our results suggest that naturally occurring Xan is a chromophore capable of photosensitization and photooxidation of lens proteins. Furthermore, this compound could play a role in age-related cataractogenesis.

Research on life stress has been characterized by inconsistent results, which some researchers attribute to different assessment methodologies. Generally, studies have used either self-report checklists or investigator-based interviews. To test whether different results are derived from these approaches, the authors compared information from a self-report measure of life stress with the additional data available from a follow-up investigator-based measure in prospectively predicting the outcome of treatment for recurrent major depression. The 2 approaches produced different results, with investigator-based life events predicting lower probability of remission and self-report life events either predicting increased likelihood of remission or not predicting at all. The results demonstrated that methodology may account for some of the inconsistencies in the life stress literature.

To determine the uptake, location and fluorescence of hypericin, the active ingredient in St. John's Wort, in situ in the isolated intact calf lens.The absorption and fluorescence spectra of hypericin 10(-5 ) M were measured in DMSO/phosphate buffer, pH 7.4) [PBS] (1/10 in volume) in the presence of alpha-crystallin (0.5 and 1.1 mg/ml). Bovine lenses were incubated in the dark for 24 hours in 10(-4) M hypericin in a DMSO/PBS (1/10 in volume) mixture. Diffused hypericin fluorescence emission was detected with a fluorescence stereomicroscope from the PBS washed lens surface. A lens-holder specially built for front-surface excitation-detection was used to measure fluorescence emission and excitation spectra of intact lenses incubated with hypericin solutions.As increasing concentrations of alpha-crystallin were added, the absorption and fluorescence spectra of hypericin in DMSO/PBS (1/10 in volume) changed, indicating a binding between the chromophore and the lens protein. Fluorescence emission spectra detected from the lens surface (lambda( em) = 601 and 651 nm; lambda(exc) = 550 nm) confirmed that hypericin does bind to the ocular tissues.The results we obtained in simplified model systems can provide clues to investigate the effects of hypericin on lens properties in physiological conditions. Hypericin could in fact bind to lens protein thus increasing the retention time of hypericin in the eye and possibly altering a-crystallin properties as a chaperone. Should therefore hypericin be taken up by the lens, this can be detected, non-invasively by its fluorescence. Therefore, ophthalmologists may use a slit-lamp or scanning fluorometry to monitor the uptake of hypericin in the eyes of patients using St. John's Wort or receiving high doses of hypericin while undergoing photodynamic therapy.

Although it is generally accepted that social risk factors predict delays in early cognitive and language development, there is less agreement about how to represent such associations statistically. Using data collected prospectively on 87 African American children during their first 4 years, this study examined 3 analytic methods for describing a child's level of social risk: (a) individual risk variables, (b) factor scores derived from those risk variables, and (c) a risk index computed by tallying the number of risk conditions present. Comparisons indicated that the individual-risk-variables approach provides better overall prediction of developmental outcomes at a particular age but is less useful in predicting developmental patterns. The risk-factor approach provides good prediction of developmental trajectories when sample sizes are moderate to large. Finally, the risk-index approach is useful for relating social risk to developmental patterns when a large number of risk variables are assessed with a small sample or when other constructs are of primary interest.

The tryptophan metabolite xanthurenic acid (Xan) has been isolated from aged human cataractous lenses. The photophysical properties of Xan were examined to determine if it is a potential chromophore for age-related cataractogenesis. We found that Xan produces singlet oxygen (psi delta = 0.17 in CD3OD) with the same efficiency as the lenticular chromophore N-formyl kynurenine and quenches singlet oxygen at a rate similar (2.1 x 10(7); CD3OD) to other tryptophan metabolites found in the eye. As the mechanisms of induction of cataracts may also involve redox reactions, the interactions of hydrated electrons (e(aq)-), the azide radical (N3*) and hydroxyl radical (OH*) with Xan were studied using the technique of pulse radiolysis. The reaction rate constants of e(aq)-, N3* and OH* with Xan were found to be of the same order of magnitude as other tryptophan metabolites. The rate constant for reaction of Xan with e(aq)- solvated electrons was found to be diffusion controlled (k = 1.43 x 10(10) M(-1) s(-1); the reaction with N3* was very fast (k = 4.0 x 10(9) M(-1) s(-1)); and with OH* was also near diffusion controlled (k = 1.0 x 10(10) M(-1) s(-1)). Superoxide O2*- production by irradiated Xan in methanol was detected by electron paramagnetic resonance and substantiated by determining that the enhanced rate of oxygen consumption of Xan irradiated in the presence of furfuryl alcohol was lowered by superoxide dismutase.

Previous work has demonstrated that melatonin inhibits the growth of both dermal and uveal melanoma cells. Recent clinical trials have found that melatonin is an efficacious treatment for metastatic dermal melanoma. The goal of this study was to provide further insight into the oncostatic mechanism(s) of melatonin. The inhibition of the growth of uveal melanoma cells is dose-dependent (0.1-10 nM) within the range of endogenous melatonin concentrations (2 nM) found in the human aqueous humor. We know that this inhibition of growth is receptor-mediated, at least in part, because uveal melanoma cell growth was also blocked by the agonists of melatonin receptors. There are two known membrane receptors for melatonin (Mel(1a) and Mel(1b)) and one known nuclear receptor (Mel2). To determine if singlet oxygen production and/or quenching contributed to the growth inhibition of melatonin, we examined the photophysical properties of melatonin and its agonists. Using flash photolysis, we determined that melatonin and its membrane receptor agonist 6-chloromelatonin (Mel(1a-b), Lilly, Indianapolis, IN) produced very little singlet oxygen (psidelta = 0.073 and psidelta = 0.01, respectively). There was no detectable singlet oxygen phosphorescence at 1,270 nm for the nuclear receptor agonist CG-52608 (Mel2, Novartis, Basel, Switzerland). In contrast, the agonist of the Mel(1b) receptor, S-20098 (Servier, Paris, France), produced singlet oxygen with a quantum efficiency of psidelta = 0.34. Singlet oxygen was quenched by melatonin and 6-chloromelatonin at approximately the same rate (6.1 x 10(7) M(-1)s(-1) and 6.0 x 10(7) M(-1)s(-1) in CD3OD), while the rate of quenching for the nuclear receptor agonist CG-52608 and membrane receptor agonist S-20098 was less (2.2 x 10(7) M(-1)s(-1) and 1.5 x 10(7) M(-1) s(-1), respectively). It appears that the production of singlet oxygen by melatonin would not be sufficient to directly block the proliferation of melanoma cells, but may activate gene products that could contribute to the oncostatic effect.

Hypericin is the active ingredient in the over the counter antidepressant medication St. John's Wort. Hypericin produces singlet oxygen and other excited state intermediates that indicate it should be a very efficient phototoxic agent in the eye. Furthermore it absorbs in the UV and visible range, which means it can potentially damage both the lens and the retina. Lens alpha-crystallin, isolated from calf lenses, was irradiated in the presence of hypericin (5 x 10(-5) M, 10 mM ammonium bicarbonate, pH 7.0) and in the presence and absence of light (300 nm, 24 mW/cm2). Hypericin-induced photosensitized photopolymerization as assessed by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Further analysis of the oxidative changes occurring in alpha-crystallin using mass spectrometry showed specific oxidation of methionine, tryptophan and histidine residues, which increased with irradiation time. Hypericin did not damage the lens protein in the dark. Damage to alpha-crystallin could undermine the integrity of the lens directly by protein denaturation and indirectly by disturbing chaperone function. Therefore, in the presence of light, hypericin can induce changes in lens protein that could lead to the formation of cataracts. Appropriate precautions should be taken to protect the eye from intense sunlight while on this antidepressant medication.