Christopher K. Hwang

Melatonin: An underappreciated player in retinal physiology and pathophysiology

In the vertebrate retina, melatonin is synthesized by the photoreceptors with high levels of melatonin at night and lower levels during the day. Melatonin exerts its influence by interacting with a family of G-protein-coupled receptors that are negatively coupled with adenylyl cyclase. Melatonin receptors belonging to the subtypes MT(1) and MT(2) have been identified in the mammalian retina. MT(1) and MT(2) receptors are found in all layers of the neural retina and in the retinal pigmented epithelium. Melatonin in the eye is believed to be involved in the modulation of many important retinal functions; it can modulate the electroretinogram (ERG), and administration of exogenous melatonin increases light-induced photoreceptor degeneration. Melatonin may also have protective effects on retinal pigment epithelial cells, photoreceptors and ganglion cells. A series of studies have implicated melatonin in the pathogenesis of age-related macular degeneration, and melatonin administration may represent a useful approach to prevent and treat glaucoma. Melatonin is used by millions of people around the world to retard aging, improve sleep performance, mitigate jet lag symptoms, and treat depression. Administration of exogenous melatonin at night may also be beneficial for ocular health, but additional investigation is needed to establish its potential.

Outcomes after Intravitreal Bevacizumab versus Laser Photocoagulation for Retinopathy of Prematurity: A 5-Year Retrospective Analysis.

PURPOSE To determine the relative effectiveness, major complications, and refractive errors associated with intravitreal bevacizumab (IVB) versus panretinal photocoagulation (PRP) to treat type 1 retinopathy of prematurity (ROP). DESIGN Retrospective case series. PARTICIPANTS Consecutive infants with type 1 ROP who received either IVB or PRP and had at least 6 months of follow-up. METHODS The data from infants treated with either IVB or PRP for type 1 ROP between 2008 and 2012 were recorded from 2 medical centers in Atlanta, Georgia. MAIN OUTCOME MEASURES Recurrence rate, complication rate, and refractive error. RESULTS A total of 54 eyes (28 patients) with type 1 ROP were evaluated: 22 eyes (11 patients) received IVB, and 32 eyes (17 patients) received PRP. Among the 22 eyes treated with IVB, 16 eyes had zone I ROP and 6 eyes had posterior zone II ROP. The number of zone I and II ROP eyes treated with PRP were 5 and 27, respectively. Mean gestational age, birth weight, postmenstrual age at initial treatment, and follow-up period for the infants receiving IVB were 24.2 weeks, 668.1 g, 35.1 weeks, and 21.7 weeks, respectively, and for the infants receiving PRP, these were 24.8 weeks, 701.4 g, 36.1 weeks, and 34.5 weeks, respectively. Retinopathy of prematurity recurred in 3 (14%) of 22 IVB-treated eyes and in 1 (3%) of 32 PRP-treated eyes. Neither retinal detachment nor macular ectopia developed in any of the IVB-treated eyes. In PRP-treated eyes, retinal detachment developed in only 1 eye and macular ectopia developed in 5 eyes. Mean spherical equivalent and postgestational age at the last refraction for IVB-treated eyes were -2.4 diopters (D) and 22.4 months, respectively, and for PRP-treated eyes, these were -5.3 D and 37.1 months, respectively. Mean spherical equivalent for zone I ROP eyes treated with IVB and PRP were -3.7 D and -10.1 D, respectively, and for zone II ROP eyes, these were 0.6 D and -4.7 D, respectively. CONCLUSIONS Both IVB and PRP are effective treatment options for type 1 ROP with low complication rates. IVB was associated with less myopia than PRP, although longer follow-up was available for PRP.

Rural diabetes prevalence quintuples over twenty-five years in low- and middle-income countries: a systematic review and meta-analysis.

AIMS To verify the assertions that diabetes pandemic may be spreading across rural parts of low- and middle-income countries (LMICs), we performed a systematic review of published studies reporting diabetes prevalence in rural parts of LMICs. METHODS Electronic databases (EMBASE and MEDLINE) were searched for papers published from 1990 to 2011. Two independent reviewers screened the articles using structured criteria for inclusion and performed full-text reviews. Pooled prevalence of diabetes was estimated using meta-analysis. Potential factors influencing the estimates were identified by meta-regression and used for sensitivity analyses. RESULTS Rural prevalence of diabetes of LMICs was 5.6% (95% CI=4.6-6.6), and similar between men and women. This estimate remained robust in separate sensitivity analyses accounting for study quality, level of heterogeneity, age, and sex. In a multivariate meta-regression analysis, pooled prevalence varied by study year and region. Diabetes prevalence increased over time, from 1.8% (1.0-2.6) in 1985-1989, 5.0% (3.8-6.3) in 1990-1994, 5.2% (4.1-6.2) in 1995-1999, 6.4% (5.1-7.7) in 2000-2004, and to 8.6% (6.4-10.7) for 2005-2010 (p=0.001 for secular trend). CONCLUSIONS Prevalence of diabetes in rural parts of LMICs has risen dramatically. As 55% of LMIC populations live in rural areas, this trend has enormous implications for the global burden of diabetes.

Dopamine D4 receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina

In the mammalian retina, dopamine binding to the dopamine D4 receptor (D4R) affects a light‐sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark‐adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D4R. The present investigation provides evidence that D4R activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild‐type mouse retina. Also, rhythms in the Ca2+‐stimulated AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D4R. Pharmacologically activating the D4R 4 h before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the D4R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D4R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina.

Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells

Spatial variation in light intensity, called spatial contrast, comprises much of the visual information perceived by mammals, and the relative ability to detect contrast is referred to as contrast sensitivity (Purves et al., 2012). Recently, retinal dopamine D4 receptors (D4Rs) have been implicated in modulating contrast sensitivity (Jackson et al., 2012); however, the cellular and molecular mechanisms have not been elucidated. Our study demonstrates a circadian rhythm of contrast sensitivity that peaks during the daytime, and that its regulation involves interactions of D4Rs, the clock gene Npas2, and the clock-controlled gene adenylyl cyclase 1 (Adcy1) in a subset of retinal ganglion cells (RGCs). Targeted disruption of the gene encoding D4Rs reduces the amplitude of the contrast sensitivity rhythm by reducing daytime sensitivity and abolishes the rhythmic expression of Npas2 and Adcy1 mRNA in the ganglion cell layer (GCL) of the retina. Npas2−/− and Adcy1−/− mice show strikingly similar reductions in the contrast sensitivity rhythm to that in mice lacking D4Rs. Moreover, Adcy1 transcript rhythms were abolished in the GCL of Npas2−/− mice. Luciferase reporter assays demonstrated that the Adcy1 promoter is selectively activated by neuronal PAS-domain protein 2 (NPAS2)/BMAL1. Our results indicate that the contrast sensitivity rhythm is modulated by D4Rs via a signaling pathway that involves NPAS2-mediated circadian regulation of Adcy1. Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing.

Global rural diabetes prevalence: A systematic review and meta-analysis covering 1990–2012

AIM To investigate diabetes prevalence in rural areas globally and how it has changed over time in high-income countries (HIC) and low-middle income countries (LMIC). METHODS We systematically searched four electronic databases (MEDLINE, EMBASE, Cochrane Library, and CINAHL) for studies reporting rural prevalence of diabetes between January 1990 and January 2012. We used random effect meta-analysis to estimate pooled prevalence and metaregression to identify factors that may be associated with our estimates. FINDINGS We included 109 population-based surveys involving 1,100,746 individuals. Pooled global rural prevalence of diabetes was 6.8% (95% confidence intervals: 6.1-7.6) with no gender difference. Considering five-year increments between 1985 and 2011, when studies were conducted, global rural prevalence was 5.7% (3.5-7.9) during 1985-1989 and 8.7% (6.8-10.7) during 2005-2011. In LMICs, rural diabetes prevalence was 1.8% (1.0-2.6) during 1985-1989 and 7.5% (5.6-9.5) during 2005-2011. In HICs, rural diabetes prevalence was 8.2% (6.0-10.4) during 1985-1989 and 14.3% (8.7-20) in the most recent period. CONCLUSION Diabetes prevalence has increased in all rural areas globally but relative growth was faster in LMIC than HIC rural areas. These data suggest a need to expand diabetes surveillance to rural areas using standardized measures, as well as the need to devise and deploy appropriate prevention and control interventions.

Spontaneous dissection of the superior mesenteric artery.

We describe a case of spontaneous dissection and thrombosis of the superior mesenteric artery in a 54-year-old man who presented with new onset of hypertension and epigastric pain. Initial unsuccessful treatment with catheter-directed thrombolysis was followed by surgical intervention. In cases in which an extensive intimectomy is performed, early institution of antiplatelet therapy or anticoagulation may be necessary to preserve vessel patency due to the presence of a prothrombotic surface and compromised outflow.

pY RNA1-s2: A Highly Retina-Enriched Small RNA That Selectively Binds to Matrin 3 (Matr3)

The purpose of this study was to expand our knowledge of small RNAs, which are known to function within protein complexes to modulate the transcriptional output of the cell. Here we describe two previously unrecognized, small RNAs, termed pY RNA1-s1 and pY RNA1-s2 (processed Y RNA1-stem −1 and −2), thereby expanding the list of known small RNAs. pY RNA1-s1 and pY RNA1-s2 were discovered by RNA sequencing and found to be 20-fold more abundant in the retina than in 14 other rat tissues. Retinal expression of pY RNAs is highly conserved, including expression in the human retina, and occurs in all retinal cell layers. Mass spectrometric analysis of pY RNA1-S2 binding proteins in retina indicates that pY RNA1-s2 selectively binds the nuclear matrix protein Matrin 3 (Matr3) and to a lesser degree to hnrpul1 (heterogeneous nuclear ribonucleoprotein U-like protein). In contrast, pY RNA1-s1 does not bind these proteins. Accordingly, the molecular mechanism of action of pY RNA1-s2 is likely be through an action involving Matr3; this 95 kDa protein has two RNA recognition motifs (RRMs) and is implicated in transcription and RNA-editing. The high affinity binding of pY RNA1-s2 to Matr3 is strongly dependent on the sequence of the RNA and both RRMs of Matr3. Related studies also indicate that elements outside of the RRM region contribute to binding specificity and that phosphorylation enhances pY RNA-s2/Matr3 binding. These observations are of significance because they reveal that a previously unrecognized small RNA, pY RNA1-s2, binds selectively to Matr3. Hypothetically, pY RNA1-S2 might act to modulate cellular function through this molecular mechanism. The retinal enrichment of pY RNA1-s2 provides reason to suspect that the pY RNA1-s2/Matr3 interaction could play a role in vision.

Residual intraretinal retinoblastoma after chemoreduction failure

Over the past decade, chemoreduction has become the treatment of choice for the initial management of retinoblastoma1. Yet despite its established use, chemoreduction has not been able to treat diffuse infiltrating retinoblastoma, the least common subtype of retinoblastoma1. Herein we report two cases in which residual intraretinal retinoblastoma exhibiting flat and diffuse infiltration was found on pathological exam after a chemoreduction failure. The chemoreduction reduced some of the tumor and unmasked the intraretinal component.

Diffuse large B cell lymphoma of the eyelid in a patient with AIDS

A 49-year-old man was evaluated for left jaw pain and swelling. He had a left neck mass that he noticed a week prior to presentation, which had rapidly enlarged and become painful. The patient also had a 2-month history of an enlarging left lower eyelid mass (figure 1). The patient denied fevers, chills or weight loss, but admitted to having night sweats. He had no recent history of oral abscesses or dental procedures and denied having any ocular pain, dysphagia, dypsnea or difficulty breathing. He denied having a history of HIV. Figure 1 The rapidly enlarging mass of the left lower eyelid had a smooth surface and was moderately tender to palpation. CT of the head and neck revealed a large soft tissue mass in the left lower eyelid, measuring 5×4 cm. The mass extended into the superomedial orbit, compressing and displacing the globe laterally. Additionally, the CT revealed a 5×5-cm neck mass with central necrosis, as well as enlarged submental and bilateral jugular lymph nodes. The findings were suspicious for an abscess, and the patient underwent biopsy with incision and drainage of the neck mass and biopsy of the left lower eyelid mass. Cultures from the neck mass were negative. The patient gave permission for a laboratory testing for HIV, and it showed that he was positive with a CD4 count of 187/mm3 and a viral load of 131 000 copies/ml. Microscopic examination of the eyelid specimen was performed (figure 2A, B). Special stains for fungi and bacteria including acid-fast bacilli were negative. Immunohistochemical stains were positive for CD45, CD68 and Ki-67 in many cells with Ki-67 cell fraction of 50% (figure 2D), CD20 in …