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Introduction This chapter describes advances in gamma-ray burst (GRB) research during the time of the Burst and Transient Source Experiment (BATSE), which was proposed to NASA in 1978, launched into Earth orbit by the Space Shuttle Atlantis in April 1991 as part of the Compton Gamma Ray Observatory (CGRO) , and de-orbited in June 2000. The chapter focuses primarily on BATSE results, although other advances during this time are also discussed. BATSE was the first large, comprehensive experiment specifically designed to study GRBs. State of the field in 1991 In the two decades prior to BATSE, and following the initial discovery and observations of GRBs with the Vela spacecraft (see also Chapter 1), considerable observational progress was made by means of other spacecraft. In the 1970s and 1980s, several comprehensive catalogs of GRB time profiles were obtained with the Konus instruments on the Venera spacecraft (Mazets et al. 1981a). Perhaps the most accurate spectrum of a GRB at the time was made over a wide energy range by observations from the gamma-ray spectrometer on the Apollo 16 spacecraft (Metzger et al. 1974). Observations of GRBs were also made by detectors on many other spacecraft designed for other types of research. These included the proportional counters on the UHURU X-ray astronomy spacecraft (R. Harnden, private communication), solar instruments ( OSO -7), lunar and planetary X-ray and gamma-ray instruments, and charged particle detectors designed for magnetospheric studies, such as IMP-6 and IMP-7 (e.g., Cline et al. 1973).

To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations.Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array.While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with "L/M interchange" mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic.The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy.

Plasma instabilities excited in collisionless shocks are responsible for particle acceleration, generation of magnetic fields , and associated radiation. We have investigated the particle acceleration and shock structure associated with an unmagnetized relativistic jet propagating into an unmagnetized plasma. Cold jet electrons are thermalized and slowed while the ambient electrons are swept up to create a partially developed hydrodynamic-like shock structure. The shock structure depends on the composition of the jet and ambient plasma (electron-positron or electron-ions). Strong electromagnetic fields are generated in the reverse , jet shock and provide an emission site. These magnetic fields contribute to the electron's transverse deflection behind the shock. We have calculated, self-consistently, the radiation from electrons accelerated in the turbulent magnetic fields. We found that the synthetic spectra depend on the Lorentz factor of the jet, its thermal temperature and strength of the generated magnetic fields. The detailed properties of the radiation are important for understanding the complex time evolution and/or spectral structure in gamma-ray bursts, relativistic jet shocks, and supernova remnants

The BATSE experiment on the Compton Gamma-ray Observatory was the first large detector system specifically designed for the study of gamma-ray bursts. The eight large-area detectors allowed full-sky coverage and were optimized to operate in the energy region of the peak emission of most GRBs. BATSE provided detailed observations of the temporal and spectral characteristics of large samples of GRBs, and it was the first experiment to provide rapid notifications of the coarse location of many them. It also provided strong evidence for the cosmological distances to GRBs through the observation of the sky distribution and intensity distribution of numerous GRBs. The large number of GRBs observed with the high- sensitivity BATSE detectors continues to provide a database of GRB spectral and temporal properties in the primary energy range of GRB emission that will likely not be exceeded for at least another decade. The origin and development of the BATSE experiment, some highlights from the mission and its continuing legacy are described in this paper.

Purpose To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Design Prospective, observational case series. Methods We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6 , 2 brothers with Oguchi disease caused by mutations in GRK1 , and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Results Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. Conclusions The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus.

[1] Terrestrial Gamma-ray Flashes (TGFs) are brief pulses of energetic radiation that correlate with thunderstorms and lightning. Most TGFs are observed as gamma-ray pulses; less frequently they can be observed as electrons and positrons that travel along the geomagnetic field line from the source to the detector. In this paper we predict where electron TGFs should be observed by tracing geomagnetic field lines from likely TGF sources and determining the intersections with satellite orbits. TGF source locations are based upon lightning maps by the Lightning Imaging Sensor (LIS) and the Optical Transient Detector (OTD). Predictions are made both for existing spacecraft with instruments observing TGFs and for other orbits. We compare the predictions to the locations of TGFs that have been observed as electron TGFs. 12 of the 13 known electron TGFs are within the predicted high-rate regions. Based on the predicted location maps of electron TGFs, we find that electron TGFs should sometimes be observed above areas with low lightning activity and that electron TGFs are best observed at low altitudes (below approximately 1000 km).

We present systematic spectral analyses of GRBs detected by the Fermi Gamma-Ray Burst Monitor (GBM) during its first two years of operation. This catalog contains two types of spectra extracted from 487 GRBs, and by fitting four different spectral models, this results in a compendium of over 3800 spectra. The models were selected based on their empirical importance to the spectral shape of many GRBs, and the analysis performed was devised to be as thorough and objective as possible. We describe in detail our procedure and criteria for the analyses, and present the bulk results in the form of parameter distributions. This catalog should be considered an official product from the Fermi GBM Science Team, and the data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center (HEASARC)., Comment: 43 pages, 24 Figures, accepted to ApJ Supplements; http://heasarc.gsfc.nasa.gov/W3Browse/fermi/fermigbrst.html

Background: Mutations in the human peripherin/retinal degeneration slow (rds) gene have been found in patients with macular dystrophies as well as in those with autosomal dominant retinitis pigmentosa. The authors studied the clinical features in members of two families with autosomal dominant retinitis pigmentosa and a previously unreported mutation in the peripherin/rds gene. Methods: Affected family members underwent a clinical ophthalmic examination and electrophysiologic and psychophysical testing. Available family members were evaluated for a mutation in the peripherin/rds gene. Results: A mutation in codon 216 of the peripherin/rds gene, resulting in a substitution of the amino acid serine for proline, was found to segregate with retinitis Pigmentosa in these two families. Ocular features of this mutation include a later onset of more notable ophthalmoscopic, electrophysiologic, and psychophysical abnormalities of the retina, an atrophic-appearing foveal lesion, and extrafoveal atrophic and hyperpigmented degenerative retinal changes, which were found more posteriorly than usually seen in patients with retinitis pigmentosa. Visual field testing showed a partial ring scotoma or pear-shaped configuration of the remaining portions of the peripheral fields. Conclusion: A previously undescribed mutation in the peripherin/rds gene is responsible for an autosomal dominant retinitis pigmentosa phenotype. This phenotype tends to be associated with the development of an atrophic-appearing foveal lesion, more posterior distribution of pigmentary changes involving the vascular arcades, the presence of a partial ring scotoma or a pear-shaped configuration of the peripheral visual field, and a later onset of more extensive retinal structural and functional impairment.

The non-collimated detectors of BATSE (Burst And Transient Source Experiment) on the Compton Gamma Ray Observatory (CGRO) can be used as a high sensitivity hard X-ray and low energy gamma-ray all-sky imager in the energy range between 20 keV and 2 MeV. The fluxes from sources in the sky are modulated as the spacecraft orbits the Earth. The CGRO orbital precession further allows sampling of the sky in strips corresponding to the limb of the Earth at any given time. The modulation data are transformed into images by various reconstruction methods. High sensitivity images of location accuracy of about 0.1/spl deg/ and source separation of about 1/spl deg/ are obtained. >

We compared the prevalence of atrophic-appearing macular lesions between black and white patients with isolated or various genetic types of retinitis pigmentosa to determine if an appreciable difference existed between these two groups. The study included 720 patients of whom 138 (19.2%) were black patients from 115 families and 582 (80.8%) were white patients from 478 families. A logistic regression analysis combining isolated and all genetic types but randomly selecting one patient per family showed a statistically significant difference in the prevalence of atrophic-appearing macular lesions between black and white patients for the right eye (P = .0012) and left eye (P = .002). When considering either all patients or one patient per family, the estimated odds ratios were approximately 2.0 for blacks relative to whites. Our findings indicate that black patients with retinitis pigmentosa are approximately twice as likely as white patients to develop an atrophic-appearing macular lesion. This observation has implications for the prognosis of central visual function in such patients.

Detectors aboard the Compton Gamma Ray Observatory have observed an unexplained terrestrial phenomenon: brief, intense flashes of gamma rays. These flashes must originate in the atmosphere at altitudes above at least 30 kilometers in order to escape atmospheric absorption and reach the orbiting detectors. At least a dozen such events have been detected over the past 2 years. The photon spectra from the events are very hard (peaking in the high-energy portion of the spectrum) and are consistent with bremsstrahlung emission from energetic (million-electron volt) electrons. The most likely origin of these high-energy electrons, although speculative at this time, is a rare type of high-altitude electrical discharge above thunderstorm regions.

Purpose: Clinical evaluation of cystoid macular edema (CME), known to occur in patients with retinitis pigmentosa (RP), is based on the presence of vascular leakage on fluorescein angiography. Due to an inability to quantitatively assess retinal thickening, the degree of thickening from fluid accumulation and its relation to fluorescein dye leakage into the extravascular retinal space has not been established. The relationship between fluorescein dye leakage and foveal thickening and the effect of methazolamide treatment was studied. Methods: The retinal thickness analyzer was used to measure the degree of thickening in six patients with RP and CME. A laser beam was projected at an oblique angle to the retina, and images of the intersection of the laser slit with the anterior and posterior retinal surfaces were recorded. The digitized images were analyzed using a dedicated software program to provide quantitative measurements of retinal thickness. Routine fluorescein angiography was performed. Results: The amount of fluorescein dye leakage was not indicative of the degree of retinal thickening due to fluid accumulation. Foveal thickening and fluorescein dye leakage were reduced in five of six eyes after methazolamide treatment. Eyes with moderate thickening reversed to normal, whereas eyes with severe thickening showed only a minimal reduction in thickness. Concuslon: Retinal thickness measurement is a useful method of evaluating both the extent of and changes in retinal thickness after carbonic anhydrase treatment.

Background Prolongation in recovery of rod thresholds has been demonstrated in Stargardt's dystrophy. One possible explanation for this finding includes an impairment of vitamin A transport by the retinal pigment epithelium (RPE). By delivering an increased amount of vitamin A to the RPE, it might be possible to overcome a relative deficiency of vitamin A utilization or transport, and thus improve rod dark adaptation. Methods Baseline dark-adapted rod final thresholds were measured for five patients with Stargardt's dystrophy after 60 minutes of dark adaptation. A full dark-adaptation curve was then measured after exposure to a bleaching light for 5 minutes. Time of recovery to within 0.2 log units of the prebleach dark-adapted rod threshold was determined. Each subject then took a 14- to 18-day course of oral vitamin A, 50,000 IU daily. Dark adaptation was then reassessed using the same pretreatment protocol. Results Before treatment, all five patients had a prolongation of their rod recovery curve. There was no statistically significant difference between subjects in mean time taken to reach prebleach rod baseline thresholds before and after vitamin A treatment. Conclusions These findings do not rule out the possibility that a delay in rod dark adaptation in Stargardt's dystrophy results from an inability to transport vitamin A from the RPE to photoreceptor cells. Nevertheless, a high dose of oral vitamin A taken for at least 14 days did not provide any objective improvement in dark-adaptation function in five such patients.

Telescopes must respond quickly to pinpoint transient gamma-ray bursts and pick up their afterglow. Mysterious 'dark' bursts seemed to produce no light at optical wavelengths, but a faint signal has now been detected.

A 46-year-old woman with a vitelliform macular lesion secondary to desferrioxamine retinal toxicity in the right eye was treated with brinzolamide 1% ophthalmic drops three times a day. A spectral-domain optical coherence tomography (SD-OCT) unit was used to monitor any changes in the macular lesion. Two months after starting the eye drops, the SD-OCT showed a notable improvement in the vitelliform macular lesion’s thickness. Six months later, further improvement was noted in the macular lesion thickness on SD-OCT testing in the right eye. Best-corrected visual acuity was initially 1.00 logarithm of the minimum angle of resolution (20/200 on a Snellen acuity chart) in the right eye and 0.14 logarithm of the minimum angle of resolution (20/25 −2 ) in the left eye. After 6 months of treatment, visual acuity was 0.92 (20/200 +1 ) in the right eye and 0.08 (20/25 +1 ) in the left eye. The use of brinzolamide 1% was associated with a marked reduction in a vitelliform macular lesion on SD-OCT testing secondary to desferrioxamine retinal toxicity.

Mutations in the ABCA4 gene are responsible for a wide variety of retinal dystrophy phenotypes, such as autosomal recessive Stargardt disease (STGD1),1 cone-rod dystrophy (CRD),2,3 and retinitis pigmentosa (RP).2,4,5 STGD1 (Mendelian Inheritance in Man 248200) is a predominantly juvenile-onset macular dystrophy associated with rapid central visual impairment, progressive bilateral atrophy of the foveal retinal pigment epithelium (Fig. 1), and frequent appearance of yellowish flecks, defined as lipofuscin deposits, around the macula or in the central and near-peripheral areas of the retina. In a large fraction of STGD1 patients, a “dark ” or “silent ” choroid is seen on fluorescein angiography that reflects the accumulation of lipofuscin throughout the retina. Figure 1. Fundus autofluorescence image of the left eye of patient 3032 harboring ABCA4 variants c.2300T>A (p.V767D) and c.735T>G (p.Y245*). This combination of ABCA4 mutations resulted in early disease onset at 5 years of age. At 16 years of age, ... More than 600 disease-associated ABCA4 variants have been identified,6 and the most frequent disease-associated ABCA4 alleles have each been described in only approximately 10% of STGD1 patients. Several studies have identified frequent “ethnic group-specific” ABCA4 alleles, such as the c.2588G>C variant resulting in a dual effect, p.G863A/delG863, as a founder mutation in Northern European patients with STGD17 and a complex allele (two variants on the same chromosome), p.L541P/A1038V, in both STGD1 and CRD patients of German origin (Fig. 2B).3,8 Complex ABCA4 alleles are not uncommon in STGD1.9 In fact, they are detected in approximately 10% of all STGD patients.10 Figure 2. Pedigrees segregating Stargardt disease. (A) An example of a pedigree with pseudodominant inheritance. Father and son are both affected with arSTGD. Mother is a carrier of a frequent c.3322C>T (p.R1108C) mutation. The new c.3522+5delG variant ... Allelic heterogeneity has substantially complicated genetic analyses of ABCA4-associated retinal disease. Efforts related to mutation detection and genotyping become especially crucial in genotype/phenotype correlation studies, in which screening of thousands of samples is needed to achieve enough statistical power because multiple rare variants and their combinations must be studied.11 We generated, at the time, a high-throughput and cost-effective screening tool, the ABCA4 genotyping microarray,12 using solid-phase arrayed primer extension (APEX) technology. The ABCA4 microarray, which has been regularly updated, contains all known disease-associated genetic variants (>600) in the ABCA4 gene. The chip has been used for efficient, systematic screening of patients with ABCA4-associated diseases13,14; it detects approximately 65% to 75% of all disease-associated alleles. On average, the array screening finds two mutations in approximately 40% of patients diagnosed with “classical” STGD1. Of the rest, one mutation is detected in 40% of patients, whereas no disease-associated allele is found in the ABCA4 coding region in 20% of screened patients.6 Direct Sanger sequencing of the entire ABCA4 coding region detects between 66% and 80% of the alleles10,15 but remains prohibitive for large patient cohorts because of time and cost constraints. Studies assessing the fraction of copy number variant (CNV) mutations, which elude PCR-based methods such as direct sequencing, (e.g., large deletions of exons and chromosomal segments), have found these in only approximately 1% of all STGD1 patients.16 Overall, variation in the ABCA4 locus has emerged as the most prevalent cause of Mendelian retinal disease because approximately 1 of 20 people across all populations carry a potential disease-associated variant in this gene.7,12,15 Recent advances in developing therapeutic applications for STGD1 in preclinical studies17,18 suggest that more comprehensive and affordable genetic screening technologies have to be implemented for molecular diagnosis and for selection of patients who would benefit from specific (especially gene-based) therapeutic modalities. Here we describe screening by NGS of a large cohort of ABCA4-associated patients who had been analyzed by the ABCA4 array and still lacked one or both mutations.

To determine the value of a topical carbonic anhydrase inhibitor on the macular thickness and function in choroideremia patients with cystoid macular edema.: Two choroideremia patients with cystoid macular edema, observed by spectral-domain optical coherence tomography, were treated with a topical form of carbonic anhydrase inhibitor. Examinations performed before and during treatment included best-corrected visual acuity by using the Early Treatment Diabetic Retinopathy Study charts and contrast sensitivity measured with briefly presented grating targets and the Pelli-Robson letter contrast sensitivity chart, microperimetry, and spectral-domain optical coherence tomography.: The 2 choroideremia patients treated with dorzolamide 2% formulation had a noticeable reduction in macular thickness by spectral-domain optical coherence tomography. This reduction was found in both eyes after 2 months of treatment. After an additional 3 months of the same treatment regimen, a more noticeable reduction in macular thickness was observed. The two study patients had improvement of their visual acuity, in at least one eye, on Early Treatment Diabetic Retinopathy Study charts, but no clinically significant changes for the other measures of visual function.: The present study shows the potential efficacy of topical dorzolamide for treating choroideremia patients with cystoid macular edema.

Congenital achromatopsia is a genetically heterogeneous, predominantly autosomal recessive, retinal disorder with a prevalence of approximately 1 in 30,000 in the general population.1 It is characterized by a lack of color discrimination, poor visual acuity, photophobia, pendular nystagmus, and abnormal photopic electroretinographic (ERG) recordings with preservation of the rod-mediated ERG. A prior report by Khan and colleagues2 showed that the rod ERG function can be modestly subnormal. The disease has been categorized into complete and incomplete achromatopsia subtypes. The incomplete (atypical) form is defined as dyschromatopsia, in which the symptoms are similar to those of the complete achromatopsia (typical) form but with less visual dysfunction.3 Patients with the complete form have nondetectable cone function on ERG testing, whereas those with the incomplete form retain some residual cone function on ERG, and often more preserved color vision and a higher level of visual acuity (up to 0.20).3–5 Funduscopy is usually normal in both forms, although not infrequently macular pigmentary mottling and even occasionally atrophic changes have been described.6 The known causes of congenital achromatopsia are all due to malfunction of the retinal phototransduction pathway. Specifically, recessive forms of achromatopsia result from the inability of cone photoreceptors to properly respond to a light stimulus by hyperpolarizing. To date, mutations in four genes have been identified to cause achromatopsia in human patients, including the α- and β-subunits of the cone cyclic nucleotide-gated ion channels, CNGA3 (ACHM2, OMIM600053) and CNGB3 (ACHM3, OMIM605080), which are located in the plasma membrane of the cone outer segments, the α-subunit of the cone photoreceptor transducin, GNAT2 (ACHM4, OMIM139340), and the catalytic α-subunit of the cone cyclic nucleotide phosphodiesterase, PDE6C (OMIM600827). The vast majority of human cases of achromatopsia are caused by mutations in either CNGA3 or CNGB3.7–11 Prior recent reports of animal studies showed that CNGB3, CNGA3, or GNAT2 knockout mice and naturally occurring dog models of achromatopsia responded well to adenoassociated virus (AAV) gene therapy. In animal models of human achromatopsia, cone ERG amplitudes recovered to nearly normal levels.12–14 These results from proof-of-principle experiments in animals with cone-directed gene therapy offer promise for eventual translation to human patients. Identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in achromatopsia patients. Previous observations regarding photoreceptor structure in achromatopsia have been limited primarily to histologic reports. In a previous report by Galezowski,15 the retinal cones were described as entirely absent. Larsen16 reported malformed foveal cones with normal cones in the peripheral retina, whereas Harrison et al.17 found misshaped and reduced numbers of retinal cones. In another report by Falls et al.,18 normal numbers of odd-shaped foveal cones and isolated numbers of cones in the peripheral retina were described. Glickstein and Heath19 found no evidence of foveal cones and reduced numbers of peripheral cones. Although genetic testing was not available at the time of these studies, they nevertheless highlight the fact that the picture of photoreceptor structure in achromatopsia is likely to be complex. Some clarity on this issue has begun to come from the use of noninvasive imaging techniques to assess photoreceptor structure in patients with achromatopsia. Optical coherence tomography (OCT), which provides excellent axial resolution, has been used to show a highly variable phenotype at the level of the photoreceptor inner segment (IS) and outer segment (OS),4,6,20,21 although the general interpretation has been that there is an absence or reduction of healthy cone structure. Adaptive optics (AO) provides high lateral resolution,22–24 and was used in a single case to examine photoreceptor structure on the single-cell level.25 The authors visualized a normal rod photoreceptor mosaic, but did not report any evidence of cone structure. These findings only confirm the complexity of the photoreceptor phenotype in achromatopsia, thus warranting further investigation. Here we used noninvasive high-resolution imaging tools (spectral domain [SD]- OCT and AO scanning laser ophthalmoscopy [SLO]) together with functional measures of vision (ERG, microperimetry [MP], and color vision) to assess photoreceptor structure and function in patients with congenital achromatopsia. We sought to correlate these findings with genetic information from the same subjects. Not only is this approach expected to provide a better understanding of the disease, but also should prove useful in identifying which patients may be most likely to benefit from participating in future gene-targeted treatment trials to rescue or restore cone photoreceptors in this group of patients. Moreover, the structural and functional assays used here would be useful for evaluating the therapeutic efficacy in patients who in fact go on to receive intervention.

We describe recent coordinated observations of lightning and terrestrial gamma ray flashes (TGFs) that provide new insight into the detailed processes that generate this thunderstorm-driven high-energy radiation. These observations include lightning mapping array measurements of the structure and development of a lightning flash that produced a TGF, and high time resolution observations of the specific lightning processes associated with three TGFs.

[1] The Gamma-Ray Burst Monitor (GBM) on the Fermi Gamma-Ray Space Telescope (Fermi) detected 50 terrestrial gamma-ray flashes (TGFs) during its first 20 months of operation. The high efficiency and large area of the GBM detectors, combined with their fine timing capabilities and relatively high throughput, allow unprecedented studies of the temporal properties of TGFs. The TGF pulses are observed to have durations as brief as ∼0.05 ms, shorter than previously measured. There is a relatively narrow distribution of pulse durations; the majority of pulses have total durations between 0.10 and 0.40 ms. In some TGF events, risetimes as short as ∼0.01 ms and falltimes as short as ∼0.03 ms are observed. Three of the 50 TGFs presented here have well-separated, double peaks. Perhaps as many as 10 other TGFs show evidence, to varying degrees, of overlapping peaks. Weak emission is seen at the leading or trailing edges of some events. Five of the 50 TGFs are considerably longer than usual; these are believed to be caused by incident electrons transported from a TGF at the geomagnetic conjugate point. TGF temporal properties can be used to discriminate between models of the origin of TGFs and also provide some basic physical properties of the TGF process.

[1] We analyze the count rates of two terrestrial gamma‐ray flashes (TGFs) detected by the Fermi Gamma‐ray Burst Monitor (GBM) with the broadband magnetic fields (1 to 300 kHz) produced by the simultaneous lightning processes. The microsecond‐scale absolute time accuracy for these data, combined with independent geolocations of the source lightning, enable this analysis with higher accuracy than previously possible. In both events, fast discharge‐like processes occur within several tens of microseconds of the gamma‐ray generation, although not with a consistent relationship. The magnetic field data also show a slower signal component produced by a source current that in both events mirrors the gamma‐ray count rate closely in shape and time. This indicates electromagnetic radiation directly associated with the gamma‐ray generation process and thus provides a new means for probing the internal physics of this enigmatic phenomenon. Citation: Cummer, S. A., G. Lu, M. S. Briggs, V. Connaughton, S. Xiong, G. J. Fishman, and J. R. Dwyer (2011), The lightning‐TGF relationship on microsecond timescales, Geophys. Res. Lett., 38, L14810, doi:10.1029/2011GL048099.

To report measures of inner retinal integrity following improvement in visual acuity and visual fields in a patient with hereditary motor and sensory neuropathy type VI (HMSN VI).The patient is a Caucasian male with HMSN VI (type 2A Charcot-Marie-Tooth disease and associated optic atrophy) and a c.1090C→T (p.R364W) mutation in the mitofusin 2 (MFN2) gene. The patient's best-corrected visual acuity improved from 20/200 (OD) and 20/400 (OS) at the initial visit to 20/25 in each eye when tested 7 years later. The visual field defects in both eyes that were present at the initial visit were absent at the follow-up visit. The structural integrity of the inner retina was assessed by an evaluation of retinal nerve fiber layer thickness (RNFLT) using optical coherence tomography (OCT), and the functional integrity was assessed by the amplitude of the photopic negative response (PhNR) of the electroretinogram (ERG). At the follow-up visit, the patient's RNFLT was less than the 5th percentile for control subjects in the superior and inferior quadrants OD and in one sector of the temporal quadrant OS, but was within normal limits elsewhere. The PhNR amplitude of each eye was below the lower limit of the normal range.The abnormally low PhNR amplitudes and abnormally thin RNFL in certain quadrants of the retina following improvement of visual acuity and visual fields to near-normal values illustrates the potential usefulness of assessing the structure and function of the inner retina in HMSN VI patients.

Melanoma-associated retinopathy (MAR) is characterized by night blindness, photopsias, and a selective reduction of the electroretinogram b-wave. In certain cases, the serum contains autoantibodies that react with ON bipolar cells, but the target of these autoantibodies has not been identified. Here we show that the primary target of autoantibodies produced in MAR patients with reduced b-wave is the TRPM1 cation channel, the newly identified transduction channel in ON bipolar cells. Sera from two well characterized MAR patients, but not from a control subject, stained human embryonic kidney cells transfected with theTRPM1gene, and Western blots probed with these MAR sera showed the expected band size (∼180 kDa). Staining of mouse and primate retina with MAR sera revealed immunoreactivity in all types of ON bipolar cells. Similar to staining for TRPM1, staining with the MAR sera was strong in dendritic tips and somas and was weak or absent in axon terminals. This staining colocalized with GFP in Grm6-GFP transgenic mice, where GFP is expressed in all and only ON bipolar cells, and also colocalized with Gαo, a marker for all types of ON bipolar cells. The staining in ON bipolar cells was confirmed to be specific to TRPM1 because MAR serum did not stain these cells in aTrpm1−/−mouse. Evidence suggests that the recognized epitope is likely intracellular, and the sera can be internalized by retinal cells. We conclude that the vision of at least some patients with MAR is compromised due to autoantibody-mediated inactivation of the TRPM1 channel.

To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease.Blood samples were obtained from 435 unrelated individuals with a clinical diagnosis of vitelliform macular dystrophy and screened for mutations in the coding sequences of BEST1. Medical records and retinal photographs of selected patients were reviewed.Nine of the 435 probands were found to have 2 plausible disease-causing variations in BEST1, while 198 individuals were found to have heterozygous variations compatible with autosomal dominant inheritance. Inheritance phase was determined in three of the recessive families. Six novel disease-causing mutations were identified among these recessive patients: Arg47Cys, IVS7-2AG, IVS7+4GA, Ile205del12ATCCTGCTCCAGAG, Pro274Arg, and Ile366delCAGGTGTGGC. Forty-four novel disease-causing mutations were identified among the patients with presumed autosomal dominant disease. The phenotype of patients with recessive alleles for BEST1 ranged from typical vitelliform lesions to extensive extramacular deposits.The authors provide evidence that two abnormal BEST1 alleles, neither of which causes macular disease alone, can act in concert to cause early-onset vitelliform macular dystrophy.

We present here our results of the temporal and spectral analysis of a sample of 52 bright and hard gamma-ray bursts (GRBs) observed with the Fermi Gamma-ray Burst Monitor (GBM) during its first year of operation (July 2008-July 2009). Our sample was selected from a total of 253 GBM GRBs based on each event peak count rate measured between 0.2 and 40MeV. The final sample comprised 34 long and 18 short GRBs. These numbers show that the GBM sample contains a much larger fraction of short GRBs, than the CGRO/BATSE data set, which we explain as the result of our (different) selection criteria and the improved GBM trigger algorithms, which favor collection of short, bright GRBs over BATSE. A first by-product of our selection methodology is the determination of a detection threshold from the GBM data alone, above which GRBs most likely will be detected in the MeV/GeV range with the Large Area Telescope (LAT) onboard Fermi. This predictor will be very useful for future multiwavelength GRB follow ups with ground and space based observatories. Further we have estimated the burst durations up to 10MeV and for the first time expanded the duration-energy relationship in the GRB light curves to high energies. We confirm that GRB durations decline with energy as a power law with index approximately -0.4, as was found earlier with the BATSE data and we also notice evidence of a possible cutoff or break at higher energies. Finally, we performed time-integrated spectral analysis of all 52 bursts and compared their spectral parameters with those obtained with the larger data sample of the BATSE data. We find that the two parameter data sets are similar and confirm that short GRBs are in general harder than longer ones., 40 pages, 11 figures, 3 tables, Submitted to ApJ

Discerning the radiative dissipation mechanism for prompt emission in gamma-ray bursts (GRBs) requires detailed spectroscopic modeling that straddles the {nu}F{sub {nu}} peak in the 100 keV-1 MeV range. Historically, empirical fits such as the popular Band function have been employed with considerable success in interpreting the observations. While extrapolations of the Band parameters can provide some physical insight into the emission mechanisms responsible for GRBs, these inferences do not provide a unique way of discerning between models. By fitting physical models directly, this degeneracy can be broken, eliminating the need for empirical functions; our analysis here offers a first step in this direction. One of the oldest, and leading, theoretical ideas for the production of the prompt signal is the synchrotron shock model. Here we explore the applicability of this model to a bright Fermi gamma-ray burst monitor (GBM) burst with a simple temporal structure, GRB 090820A. Our investigation implements, for the first time, thermal and non-thermal synchrotron emissivities in the RMFIT forward-folding spectral analysis software often used in GBM burst studies. We find that these synchrotron emissivities, together with a blackbody shape, provide at least as good a match to the data as the Band GRB spectral fitting function. more » This success is achieved in both time-integrated and time-resolved spectral fits. « less

[1] Terrestrial Gamma-ray Flashes (TGFs) are brief pulses of energetic radiation observed in low-earth orbit. They are associated with thunderstorms and lightning and have been observed both as gamma-ray and electron flashes depending on the position of the spacecraft with respect to the source. While gamma-ray TGFs are detected as short pulses lasting less than 1 ms, most TGFs seen by the Fermi Gamma-ray Burst Monitor (GBM) with durations greater than 1 ms are, instead, the result of electrons traveling from the sources along geomagnetic field lines. We perform spectral analysis of the three brightest electron TGFs detected by GBM and discover strong 511 keV positron annihilation lines, demonstrating that these electron TGFs also contain substantial positron components. This shows that pair production occurs in conjunction with some terrestrial lightning and that most likely all TGFs are injecting electron-positron beams into the near Earth environment.

In this paper we examine gamma-ray and optical data of GRB 091024, a gamma-ray burst (GRB) with an extremely long duration of T90~1020 s, as observed with the Fermi Gamma-Ray Burst Monitor (GBM). We present spectral analysis of all three distinct emission episodes using data from Fermi/GBM. Because of the long nature of this event, many ground-based optical telescopes slewed to its location within a few minutes and thus were able to observe the GRB during its active period. We compare the optical and gamma-ray light curves. Furthermore, we estimate a lower limit on the bulk Lorentz factor from the variability and spectrum of the GBM light curve and compare it with that obtained from the peak time of the forward shock of the optical afterglow. From the spectral analysis we note that, despite its unusually long duration, this burst is similar to other long GRBs, i.e. there is spectral evolution (both the peak energy and the spectral index vary with time) and spectral lags are measured. We find that the optical light curve is highly anti-correlated to the prompt gamma-ray emission, with the optical emission reaching the maximum during an epoch of quiescence in the prompt emission. We interpret this behavior as the reverse shock (optical flash), expected in the internal-external shock model of GRB emission but observed only in a handful of GRBs so far. The lower limit on the initial Lorentz factor deduced from the variability time scale ($\Gamma_{min}=195_{-110}^+{90}$)is consistent within the error to the one obtained using the peak time of the forward shock ($\Gamma_0=120$) and is also consistent with Lorentz factors of other long GRBs., Comment: accepted for publication in A&A

We report on the preliminary analysis of fast temporal fluctuations observed in hard X-ray bursts, as recorded by the Burst and Transient Source Experiment (BATSE) on the Compton Gamma Ray Observatory.

The Burst and Transient Source Experiment (BATSE) on the Compton Gamma Ray Observatory has opened a hard X-ray window of unprecedented sensitivity from 10 to several hundreds of keV which allows a fresh examination of the details of the accelerated electron spectrum during solar flares. Using the BATSE Spectroscopy detectors we have examined the low energy hard X-ray spectrum for thermal components and evidence of cutoffs in the accelerated electron spectrum.

PURPOSE: To report unusual fundus findings in two cases of melanoma-associated retinopathy. METHODS: Observational case reports. The histories of two patients with melanoma-associated retinopathy were reviewed. Sera from both patients were examined for antibodies against retinal bipolar cells. Immunofluorescence was performed on cryostat sections of unfixed normal human retinas. Sera and IgG from both patients were tested against a known melanoma-associated retinopathy patient as well as a control subject. RESULTS: Our patients had metastatic, cutaneous melanoma and a clinical syndrome consistent with melanoma-associated retinopathy. Both patients had serum antibodies that were reactive against retinal bipolar cells. They had unusual fundus changes not previously described in association with melanoma-associated retinopathy. One patient also developed vitiligo. CONCLUSION: Patients with metastatic cutaneous melanoma and melanoma-associated retinopathy may present unusual fundus lesions that may be caused by autoimmunity which is part of the clinical picture of melanoma-associated retinopathy or metastatic melanoma.

[1] We report on a search for correlations between terrestrial gamma ray flashes (TGFs) detected by the Fermi Gamma-ray Burst Monitor (GBM) and lightning strokes measured using the World Wide Lightning Location Network (WWLLN). We associate 15 of a total 50 GBM-detected TGFs with individual discharges. We establish the relative timing between the TGF and the lightning stroke to an accuracy of

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of them have their mutations identified including 26 novel changes. Comprehensive phenotyping of these patients demonstrate that the spectrum of clinical features is greater than expected and overlapped with the features of other ciliopathies; specifically Alstrom and McKusick-Kauffman syndromes.

The purpose of this study was to determine if carbonic anhydrase inhibitors can restore their efficacy after a period of discontinued use in patients with cystic foveal lesions who demonstrated subsequent worsening in the extent of their foveal cysts after initially exhibiting a favorable response to treatment.Retrospective chart review was conducted on all patients with retinitis pigmentosa or X-linked retinoschisis who were either currently on treatment or had been treated with carbonic anhydrase inhibitors for cystic macular lesions. A total of three patients were included in the study.All three patients exhibited a recurrence of their cystic macular lesions while on treatment with carbonic anhydrase inhibitors. After discontinuing treatment for a period of 1 month to 6 months, all patients showed a favorable response to retreatment as monitored with optical coherence tomography scans.The present study shows that patients who show signs of recurring macular cysts while still on treatment can have a favorable response when treatment is reinstated after a period of discontinued use of a carbonic anhydrase inhibitor.

To determine the prevalence of cystic macular oedema (CME) in patients with choroideremia (CHM) by using spectral-domain optical coherence tomography (SD-OCT). A total 16 patients affected with CHM were enroled in the study. All patients underwent a complete eye examination. SD-OCT was performed using an OPKO spectral-domain OCT/SLO instrument. The average age of the study patients was 44.0±16.0 years (range, 13–63 years). Out of the 16 patients with CHM, 10 patients (62.5%) showed a degree of CME on SD-OCT testing in at least one eye, and 8 patients (50%) showed CME in both eyes. Because of its notable prevalence, it would seem prudent to screen CHM patients by SD-OCT for the possible presence of CME and to identify those amenable to future treatment strategies for their macular oedema.

Objective To determine the efficacy of sustained topical therapy with dorzolamide hydrochloride, 2%, on visual acuity and cystic macular lesions in patients with retinitis pigmentosa and Usher syndrome. Methods In a retrospective case series at a university hospital, 64 eyes of 32 patients with retinitis pigmentosa or Usher syndrome receiving treatment with the topical dorzolamide formulation for 6 to 58 months were enrolled. Changes in visual acuity on the Early Treatment Diabetic Retinopathy Study chart and central foveal zone thickness on optical coherence tomography were measured during follow-up for the duration of treatment. Results Among the study cohort, 20 of 32 patients (63%) showed a positive response to treatment in at least 1 eye and 13 patients (41%) showed a positive response in both eyes. Four patients (20%) showed an initial response and a subsequent rebound of macular cysts. In 8 patients (25%), there was no response to treatment and the macular cysts worsened when compared with the pretreatment level. Ten patients (31%) had improvement in visual acuity by 7 or more letters in at least 1 eye at the most recent follow-up visit. Sixteen patients (67%) showed a reduction of more than 11% in the central foveal zone thickness in at least 1 eye when compared with the pretreatment level. Conclusions Patients with either retinitis pigmentosa or Usher syndrome who received treatment of cystoid macular edema with topical dorzolamide followed by an optical coherence tomography–guided strategy showed a decrease in central foveal zone thickness in most cases. Visual acuity improved in almost one-third of the cases, suggesting a potential corresponding visual benefit.

Purpose To assess the highest educational level attained by patients with Stargardt disease and clinically significant visual impairment. Design Cross-sectional assessment. Methods Patients with Stargardt disease and clinically significant visual impairment (documented best-corrected visual acuity of 20/70 or worse in each eye either before or up to the age of 22 years) were included in the study. Information concerning the highest level of education attained was obtained for all participants by an interview. Results Of the 33 participants, 32 completed high school. Either an associate's or bachelor's degree was attained by 21 patients (63.6%), whereas 3 patients (9.1%) were enrolled in college at the time of the interview. Further, a postgraduate degree (master's or doctorate) was attained by 7 patients (21.2%). Conclusions Our findings document that the potential for attaining a higher degree of academic education beyond high school does not seem to be precluded by clinically significant visual impairment in Stargardt patients. This information can be useful for visual practitioners when counseling these patients and their families.

[1] The Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope detected 12 intense terrestrial gamma ray flashes (TGFs) during its first year of observation. Typical maximum energies for most of the TGFs are ∼30 MeV, with one TGF having a 38 MeV photon; two of the TGFs are softer and longer than the others. After correcting for instrumental effects, a representative bright TGF is found to have a fluence of ∼0.7 photons cm−2. Pulses are either symmetrical or have faster risetimes than fall times; they are well fit with Gaussian or lognormal functions. The fastest risetime observed was 7 μs, constraining the source radius to be less than about 2 km from the velocity of light. TGFs with multiple pulses separated in time have been known since their discovery; the GBM sample also includes clear cases of partially overlapping pulses. Four TGFs are associated with lightning locations from the World Wide Lightning Location Network. With the several μs absolute time accuracy of GBM, the time order can be confidently identified: one TGF occurred before the lightning, two were simultaneous, and one TGF occurred after the lightning.

Changes in the response characteristics of the flash electroretinogram (ERG) of the human cone system were studied during the time course of adaptation to a cone-isolating ganzfeld background. During light adaptation, the amplitudes of the b- and i-waves increased, while the implicit time of the b-wave decreased. The amplitude of the a-wave and the implicit times of the a- and i-waves did not change systematically during light adaptation. Luminance-response functions for b-wave amplitude were obtained at discrete times following background onset and were analyzed using the hyperbolic equation R/R(max) = L(n)/(L(n) + K(n)). The increase in b-wave amplitude was characterized by increases in R(max), K, and n. The decrease in b-wave implicit time was of a similar magnitude at all flash luminances. The amplitude increase of the i-wave only occurred at moderate flash luminances. The results provide a basis for optimizing the clinical recording of cone-isolated single-flash ERGs.

Background Bardet–Biedl syndrome is a pleiotropic disorder with 14 BBS genes identified. BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 form a complex called the BBSome, which is believed to recruit Rab8 GTP to the primary cilium and promote ciliogenesis. The second group, the chaperonin-like proteins BBS6, BBS10, and BBS12, have been defined as a vertebrate-specific branch of the type II chaperonin superfamily. These may play a role in the regulation of BBSome assembly. Methods and results Using sequence analysis, the role of BBS6, 10 and 12 was assessed in the patient population comprising 93 cases from 74 families. Systemic and ocular phenotypes were defined. In the study, chaperonin-like BBS gene mutations accounted for the disease in approximately 36.5% of BBS families. A total of 38 different non-polymorphic exonic sequence variants were identified in 40.5% of BBS families (41.9% cases), of which 26 were novel (68%). Six cases had mutations present in more than one chaperonin-like BBS gene. One case with four mutations in BBS10 had a phenotype of overall greater severity. The phenotypes observed were beyond the classic BBS phenotype as they overlapped with characteristics of MKKS (congenital heart defect, vaginal atresia, hydrometrocolpos, cryptorchidism), as well as Alstrom syndrome (diabetes, hearing loss, liver abnormalities, endocrine anomalies, cardiomyopathy). Conclusions While overlap between the MKKS and BBS phenotypes has previously been reported for cases with BBS6 mutations, we also observed MKKS phenotypes involving BBS10 and BBS12 and Alstrom-like phenotypes associated with mutations in BBS1 , BBS2 , BBS6 , BBS7 , BBS9 , BBS10 and BBS12 for the first time.

Leber congenital amaurosis (LCA) is clinically described as a group of early-onset photoreceptor cell degenerations. It is usually inherited in an autosomal recessive fashion and characterized by severe impairment of visual function and nystagmus early in life. Affected individuals may have a normal-appearing fundus at an initial stage, which may be followed by retinal pigment clumping and vascular attenuation. Other fundus findings—for instance, retinal flecks,1,2 macular coloboma-like lesions,3 and chorioretinal atrophy,4—may be observed. Marked reduction or absence of retinal function measured by an electroretinogram (ERG) is characteristic. Enophthalmos, oculodigital phenomenon,5 cataract,6 keratoconus,7 and hyperopia8 have also been described. LCA is a genetically heterogeneous disease. To date, plausible disease-causing variations have been reported in 14 genes9: AIPL1, CEP290, CRB1, CRX, GUCY2D, IMPDH1, LCA5, LRAT, MERTK, RD3, RDH12, RPE65, RPGRIP1, and TULP1. Mutations in these genes account for approximately 70% of all cases of LCA. The most prevalent mutated genes are CEP290 (15%) and GUCY2D (12%).10 Interest in LCA has recently been increasing since the reports of preliminary success in phase 1 studies of gene-directed therapy in LCA patients with RPE65 mutations.11–13 Gene-directed therapy is eventually likely to be applicable for LCA patients with other genetic mutations as well. Although there is an overlap of phenotypic expressions between different genotypes, phenotypic trends in patients with the same genotype have been described for at least some mutations.14 In this study, we evaluated possible correlations between macular microstructure and various LCA genotypes for patients with mutations in RPE65 (retinal pigment epithelium-specific 65-kDa protein), CEP290 (centrosomal 290-kDa protein, also known as NPHP6), GUCY2D (guanylate cyclase 2D, also known as RETGC), or AIPL1 (arylhydrocarbon interacting receptor protein-like 1) genes, detected by spectral-domain–optical coherence tomography (SD-OCT). These types of studies are important for at least two reasons: one is to probe anatomic differences between the various LCA genotypes to understand the disease phenotypes better. Another reason is to evaluate the possibilities of viable retinal structures, including photoreceptors, to aid in predicting the potential for therapeutic success.

[1] Measurements from the Burst and Transient Source Experiment (BATSE) instrument on the Compton Gamma Ray Observatory (CGRO) are the only ones where characteristics of single terrestrial gamma ray flashes (TGFs) have been obtained thus far. However, it has been reported that the measurements suffer from significant dead time losses which complicates the analysis and raises question about earlier BATSE studies. These losses are due to the high-intensity flux combined with limitations of the time resolution of the instrument. Since these losses will affect both the spectrum and the temporal distribution of the individual TGFs, results based on BATSE data need to be revisited, including our own. We have therefore developed a Monte Carlo method to study the effects of these dead time losses. We show that the energy spectrum of TGFs becomes softer as the dead time losses increase. We also show that the time delay between the light curves of hard (E > 300 keV) and soft (E < 300 keV) photons increases significantly as the dead time losses increase. The Monte Carlo approach also enables us to identify the BATSE TGFs where the dead time effects can be corrected. These are the short-duration single-peaked TGFs. Without correcting for dead time losses we find that these short single-peak TGFs have a softer energy spectrum and larger time delay than the multipeaked TGFs. After correcting for dead time losses we perform a new analysis of production altitudes and find that the production altitude is reduced compared to analysis without dead time losses. The new production altitudes combined with dead time losses are also consistent with the apparent large time delays. Our method gives consistent results regarding production altitude and time delays and indicates that the corrected TGF intensities measured by BATSE are 3 to 4 times brighter than the uncorrected measurements would indicate. We also show that the production mechanism of these TGFs has a typical duration of 250 μs.

To evaluate macular thickness profiles using spectral-domain optical coherence tomography (SDOCT) and image segmentation in patients with chronic exposure to hydroxychloroquine.This study included eight patients with chronic exposure to hydroxychloroquine (group 1) and eight controls (group 2). Group 1 patients had no clinically evident retinal toxicity. All subjects underwent SDOCT imaging of the macula. An image segmentation technique was used to measure thickness of six retinal layers at 200 microm intervals. A mixed-effects model was used for multivariate analysis.By measuring total retinal thickness either at the central macular (2800 microm in diameter), the perifoveal region 1200-microm-width ring surrounding the central macula), or the overall macular area (5200 microm in diameter), there were no significant differences in the thickness between groups 1 and 2. On an image segmentation analysis, selective thinning of the inner plexiform+ganglion cell layers (P=0.021) was observed only in the perifoveal area of the patients in group 1 compared with that of group 2 by using the mixed-effects model analysis.Our study results suggest that chronic exposure to hydroxychloroquine is associated with thinning of the perifoveal inner retinal layers, especially in the ganglion cell and inner plexiform layers, even in the absence of functional or structural clinical changes involving the photoreceptor or retinal pigment epithelial cell layers. This may be a contributing factor as the reason most patients who have early detectable signs of drug toxicity present with paracentral or pericentral scotomas.

To determine the efficacy of sustained topical therapy with dorzolamide hydrochloride, 2%, on visual acuity and cystic macular lesions in patients with juvenile X-linked retinoschisis (XLRS).Retrospective analysis.University hospital, tertiary care referral center.Twenty-nine eyes of 15 patients with XLRS receiving treatment with the topical dorzolamide formulation for 4 to 41 months were enrolled.Changes in visual acuity, cystic macular lesions, and central foveal zone thickness on optical coherence tomography during follow-up for the duration of treatment.Among the 15 patients with XLRS, 20 eyes (69%) of 11 patients showed a positive response to treatment. Five of the 20 eyes (25%) in 3 of the 11 patients showed an initial response and a subsequent rebound of macular cysts. In 4 eyes (14%) of 3 patients, there was no response to treatment, but the macular cysts did not worsen compared with the baseline level. In 5 additional eyes (17%) of 4 patients, there was no response to treatment, and the macular cysts worsened when compared with the baseline level. Sixteen eyes (55%) of 12 patients had improvement in best-corrected visual acuity by at least 7 letters in at least 1 eye at the most recent follow-up visit. Seventeen eyes (59%) of 10 patients showed a reduction in the central foveal zone thickness in at least 1 eye when compared with the pretreatment level.Patients with XLRS have the potential to experience a beneficial effect from sustained treatment with dorzolamide, 2%.

Purpose: The effect of mydriasis on Goldmann visual field area in patients with retinitis pigmentosa has not been suitably defined. The aim of this study is to determine whether visual field area in these patients varies with pharmacologic mydriasis. Methods: Fifteen adult patients with retinitis pigmentosa were studied prospectively. Goldmann visual fields with II4e and V4e isopters were obtained in both eyes before and after full pharmacologic mydriasis of the right eye. The isopter areas were quantified and analyzed to determine the effect of mydriasis on visual field area. Results: The difference in the right eye isopter areas was compared with the difference in the left eye isopter areas using paired t tests, where the differences were computed from areas obtained before and after dilation of the right eye. Mydriasis had no significant effect on the visual field in terms of isopter area difference (II4e, P = 0.87; V4e, P = 0.45) and percent change in isopter area (II4e, P = 0.81; V4e, P = 0.24). Conclusion: Pharmacologic mydriasis had no appreciable effect on the Goldmann visual field area in a selected group of patients with retinitis pigmentosa. These findings suggest that visual fields of such patients obtained in the dilated or undilated state can be meaningfully compared.

Background: Dominantly inherited cystoid macular edema was described as a clinically distinct form of macular dystrophy with an onset at approximately age 30 years with slow progression over the ensuing decades. This is the first report of the light and electron microscopic findings in two donor eyes of one of the patients with this clinical entity. Methods: Both eyes were obtained after death and fixed within 24 hours in a buffered 4% formaldehyde-1 % glutaraldehyde solution. For light microscopy, tissue was embedded in paraffin and stained with hematoxylin-eosin, periodic acid-Schiff, colloidal iron for mucopolysaccharides, and an antibody to glial fibrillar acidic protein. For ultrastructural investigation, several blocks of choroidal/retinal tissues from the posterior pole, including both maculae, were embedded in epoxy resin and processed for transmission electron microscopy. Results: Major findings included large retinal cysts in the macula, atrophy and marked disorganization of the inner nuclear layer, advanced degeneration of Muller cells with nodular aggregates of basement membrane-like material, and a preretinal membrane. The retinal vasculature did not show excessive endothelial alterations but was surrounded by deposits of multilayered basement membrane in the perivascular space. Conclusion: The authors believe that the pathologic features of dominantly inherited cystoid macular edema are different from those of macular edema caused by other disease processes. The predominant pathologic changes affected mainly the inner nuclear layer. The possibility of a primary disease of the Muller cell is suggested.

The Long Duration Exposure Facility (LDEF), retrieved by the Space Shuttle mission STS-32 after nearly 6 yr in orbit, is the focus of a broad-based study of the radiation environment in low Earth orbit (LEO) and its effects on materials. A combination of passive techniques has been used to study this environment via detectors which were contained in experiments aboard the LDEF spacecraft and through analysis of induced radioactivities. Preliminary results for absorbed dose measurements and for induced activities in various materials are presented. A number of effects have been observed which reflect the anisotropy of the charged particle flux in low Earth orbit. Quantitative results from these measurements should provide an accurate means of confirming environmental flux models and techniques for predicting radiation encountered in future LEO missions, particularly those of extended duration.

To define the retinal pathology in an 88-year-old male affected with Goldmann-Favre syndrome with a 2 bp 5' AC splice site mutation in the NR2E3 gene.Retinal tissue from the macula and periphery was processed for immunohistochemistry. Perimacular retina was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to rhodopsin, cone cytoplasm, and cone opsins. The affected donor eye was compared to a postmortem matched normal eye.The retina was highly disorganized without laminar organization. The RPE was discontinuous in some perimacular regions. Large (1 mm) spherical electrondense melanosomes were observed in the RPE and choroid by TEM. Rods were virtually absent in the affected retina. Cones were present in the macula, but were mostly absent from the retinal periphery. In addition, cone rosettes were observed in the perimacular area. Both red/green and blue cone opsins were distributed along the entire cellular expanse of the cone photoreceptors in the affected eye, but were restricted to the cone outer segments in the control retina.The histological data obtained from the retina of an elderly male patient with Goldmann-Favre syndrome showed an absence of rods and abnormal distribution of red/green and blue cone opsins.