One-year follow-up of optical coherence tomography angiography microvascular findings: macular telangiectasia type 2 versus tamoxifen retinopathy.

PURPOSE: To compare microstructural and microvascular changes in eyes with macular telangiectasia type 2 (MacTel2) and in those with tamoxifen retinopathy (TR) at baseline and at the 1-year follow-up using optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: We followed up patients diagnosed with MacTel2 or TR for at least 1 year. We included 17 patients with MacTel2 (31 eyes) and 15 with TR (25 eyes) who discontinued tamoxifen use after a TR diagnosis. We performed OCT and OCTA at baseline and after 1 year. RESULTS: Patients with MacTel2 and TR showed intraretinal cavitation, ellipsoid zone (EZ) loss, and capillary telangiectasia in the superficial and deep plexuses. EZ disruption predominantly affected the temporal region in MacTel2 (32%) and was limited to the foveal center in TR (24%). Vascular density (VD) was significantly reduced within the deep temporal parafovea and superficial fovea in MacTel2 and TR eyes, respectively. After 1 year, the MacTel2 eyes showed enlarged EZ loss, proliferative vascular invasion, and increased VD (p = 0.021) in the temporal deep plexus compared with TR eyes. CONCLUSIONS: After 1-year follow-up, the MacTel2 eyes showed proliferative vascular remodeling, particularly in the temporal parafovea of the deep plexus with EZ loss progression, whereas the TR eyes maintained their baseline capillary rarefaction.

SYSTEMIC FACTORS AND EARLY TREATMENT RESPONSE TO INTRAVITREAL INJECTION FOR DIABETIC MACULAR EDEMA: The Role of Renal Function.

PURPOSE: To investigate the effect of systemic factors on early treatment response to intravitreal bevacizumab injection (IVBI) and intravitreal dexamethasone implant (IVDI) in patients with diabetic macular edema (DME). METHODS: We reviewed the medical records of 117 treatment naïve DME patients who underwent IVBI. We divided the patients according to their IVBI response. An IVDI was performed in patients with poor response to IVBIs. We investigated the various systemic factors of diabetic patients and examined the relationship between systemic factors and the treatment response to IVBI and IVDI. RESULTS: In a total of 117 treatment naïve DME eyes, 61 eyes (52.14%) were classified as IVBI responders. An IVDI was performed in 23 of 56 eyes with poor response to IVBI, and 17 eyes (73.91%) had a good response. Among various systemic factors of patients with diabetes, renal function (blood urea nitrogen, creatinine, and estimated glomerular filtration rate) showed a significant negative correlation with central subfield retinal thickness improvement after treatment (P < 0.05). However, there was no difference in HbA1C levels regarding the treatment response to IVBI and IVDI. CONCLUSION: Renal function was significantly worse in patients with a poor response to IVBI and IVDI. Renal function could be used as a possible predictor for treatment response in certain patients with DME. Furthermore, for patients with DME with poor responses to anti-vascular endothelial growth factor or steroid treatments, assessment of renal function could help explain the poor treatment response.

PRESERVATION OF THE FOVEAL FLAP IN MACULAR HOLE SURGERY.

PURPOSE: To investigate the impact of preserving the foveal flap on surgical outcomes of full-thickness macular hole (MH) with foveal flaps. METHODS: We retrospectively reviewed patients with Stages 2 and 3 idiopathic MH, who underwent pars plana vitrectomy by a single surgeon at Asan Medical Center from November 2011 to November 2016. In the study group, we included eyes with MH and a foveal flap on preoperative spectral domain optical coherence tomography and successfully preserved the flap during surgery. The control group included eyes with MH and an operculum in the posterior vitreous plane on preoperative optical coherence tomography. We compared the anatomical and functional surgical outcomes between these groups. RESULTS: Postoperative mean best-corrected visual acuity at the last visit was 20/25 and 20/33 in the study (9 eyes) and control (23 eyes) groups, respectively. The study group showed a significantly better postoperative best-corrected visual acuity (P < 0.05). Restoration of both the external limiting membrane and ellipsoid zone, as assessed by spectral domain optical coherence tomography, was achieved in 9 (100%) and 15 (65.2%) eyes of the study and control groups, respectively. CONCLUSION: Preserving the foveal flap might improve both functional and anatomical outcomes of vitrectomy for MHs with a foveal flap.

Correlation between Visual Function and Structural Characteristics of the Macula in Advanced Retinitis Pigmentosa.

We aimed to correlate the visual function and structural characteristics of the retina and choroid in advanced retinitis pigmentosa (RP) patients. A cross-sectional, retrospective review was conducted of medical records of 149 RP patients who reported visual field constriction on a central 30-2 Humphrey visual field chart. Using spectral domain-optical coherence tomography, central foveal thickness (CFT), ellipsoid zone (EZ) length, macular volume (MV), and submacular choroidal thickness (SMChT) were measured. A control cohort (68 eyes of 68 patients) was included for comparing the macular structure. Quantitative correlations between visual function indices [visual field index (VFI) and best-corrected visual acuity (BCVA)] and structural indices (CFT, EZ length, and SMChT) were evaluated. Mean age was 46.3 ± 15.5 years; mean illness duration was 60.7 ± 60.0 months. SMChT was thinner than that in normal controls. Per Pearson's correlation, BCVA and VFI exhibited a progressive worsening related to age and disease duration. In multivariate linear regression, BCVA and VFI were significantly correlated with CFT, EZ length, and MV at the central 1-mm area. Among RP patients with visual field constriction within 30°, VFI and BCVA closely correlate with the degree of retinal structural change, including the CFT, EZ length, and MV. SMChT uniformly decreased in this study population and exhibited no significant correlation with BCVA or VFI degree.

The Effect of Tumor Necrosis Factor-Alpha Inhibitors on Uveitis in Patients with Ankylosing Spondylitis.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis), which are the main treatment for ankylosing spondylitis (AS), have been reported not only to reduce the incidence of anterior uveitis (AU) but also to induce it, and these effects differ among the various types of TNFis in clinical use. The present study investigated the effect of TNFis on uveitis by analyzing the long-term clinical course of AU in AS patients treated with TNFi therapy. METHODS: Patients treated with at least one TNFi between January 2007 and July 2017 were reviewed, and 54 patients with at least one episode of AU were included in this study. The TNFis included anti-TNF-α antibodies (adalimumab, infliximab, and golimumab), and a soluble TNF receptor molecule (etanercept). The effect of prevention of AU, the likelihood of new-onset uveitis after the initiation of TNFi therapy, and the effects of drug switching and dose escalation were assessed. RESULTS: The first uveitis flare was observed before TNFi therapy in 39 patients and after TNFi therapy in 15 patients. Anti-TNF-α antibodies were more efficacious in decreasing the recurrence of AU than etanercept. Among patients in which uveitis first occurred after beginning TNFi therapy, patients on etanercept tended to first develop AU less than 1 year after starting the drug, and their AS tended to be well-controlled at the time of uveitis flares. Patients with a uveitis flare before their medication was switched did not recur afterwards, and five of eight patients showed no relapse after dose escalation. CONCLUSION: TNFis have various effects on AU. TNFis, particularly anti-TNF-α antibodies, should be considered in patients with AS and frequent AU relapse. Additionally, clinicians should consider whether AU is due to an absence of a therapeutic response of AS to TNFi treatment or to TNFi treatment itself, and appropriate treatment changes should be made accordingly.

Changes in the clinical features and prognostic factors of endogenous endophthalmitis: fifteen years of clinical experience in Korea.

PURPOSE: To identify changes in the clinical features, management, and prognostic factors of endogenous endophthalmitis in Korea from 1996 through 2010. METHODS: We conducted a retrospective review of medical records of patients diagnosed with endogenous endophthalmitis from January 1996 to December 2010, which was divided into 3 periods: 1996 to 2000, 2001 to 2005, and 2006 to 2010. Variables included age, source of infection, systemic conditions, initial and final visual acuities, causative organisms, and treatment. RESULTS: Endophthalmitis was identified in 80 patients (97 eyes). Diabetes (42.5%) and liver cirrhosis (20%) were the common systemic problems in these patients. Liver abscess (25%) was the most common infection focus of the endophthalmitis. Klebsiella pneumoniae (48.4%) was the common causative agent, although more recently, endophthalmitis caused by gram-positive cocci has increased in frequency. The use of vitrectomy as an initial treatment has increased during the past 5 years. Good initial visual acuity greater than counting fingers (P < 0.001), early vitrectomy in patients with initially good visual presentation (P = 0.035), and gram-positive cocci (P = 0.033) as a causative agent were significantly related to a successful visual outcome. CONCLUSION: Although the prognosis of endogenous endophthalmitis is generally poor in most patients, some eyes can have relatively good visual outcomes if treated appropriately and early enough.

The mechanism of antibacterial activity of tetrandrine against Staphylococcus aureus.

Tetrandrine (TET) is a bis-benzylisoquinoline alkaloid derived from the radix of Stephania tetrandra S. Moore. TET performs a wide spectrum of biological activities. The radix of S. tetrandrae has been used traditionally in Asia, including Korea, to treat congestive circulatory disorders and inflammatory diseases. The aim of this study was to examine the mechanism of antibacterial activity of tetrandrine against Staphylococcus aureus. The mechanism was investigated by studying the effects of TET in combination with detergent or membrane potential un-couplers. In addition, the direct involvement of peptidoglycan (PGN) was assessed in titration assays. TET activity against S. aureus was 125-250 µg/mL, and the minimum inhibitory concentration (MIC) of the two reference strains was 250 µg/mL. The OD(600) of each suspension treated with a combination of ethylenediaminetetraacetic acid (EDTA), tris(hydroxymethyl) aminomethane (TRIS), and Triton X-100 (TX) with TET (0.25×MIC) had been reduced from 43% to 96%. Additional structure-function studies on the antibacterial activity of TET in combination with other agents may lead to the discovery of more effective antibacterial agents.

A pilot study of scleral thickness in central serous chorioretinopathy using anterior segment optical coherence tomography.

The aim of this study is to compare the scleral thickness of central serous chorioretinopathy (CSC) eyes with controls using anterior segment optical coherence tomography (AS OCT). This prospective case control study included 15 patients (15 eyes) with CSC and 15 age and gender matched healthy subjects. All subjects underwent spectral domain OCT with enhanced depth imaging and swept source AS OCT of temporal sclera. We investigated difference in scleral thickness between the two groups and relationship between choroidal and scleral thickness. Among the 15 eyes in the study group, 1 eye had acute CSC, 4 had recurrent CSC, 7 had inactive CSC, and 3 had chronic CSC. There was no significant difference in terms of age, gender, axial length and spherical equivalent between the two groups. The choroidal and scleral thickness of the study group were significantly greater than those of the control group (P < 0.001, P = 0.034). Choroidal thickness was positively correlated with scleral thickness (P = 0.031). A thick sclera along with a thick choroid were demonstrated in CSC eyes using AS OCT. Scleral characteristics might be involved in the pathogenesis of CSC by affecting outflow resistance of venous drainage in choroidal circulation.

Long-Term Visual/Anatomic Outcome in Patients with Fovea-Involving Fibrovascular Pigment Epithelium Detachment Presenting Choroidal Neovascularization on Optical Coherence Tomography Angiography.

BACKGROUND: To evaluate long-term visual/anatomic outcome after anti-vascular endothelial growth factor (anti-VEGF) therapy in patients with fovea-involving fibrovascular pigment epithelium detachment (PED) presenting with choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA). METHODS: Patients with fibrovascular PED or subretinal CNV confirmed by OCTA who were treated by a relaxed treat-and-extend regimen for 2 years were retrospectively reviewed. The best-corrected visual acuity (BCVA) and central subfield retinal thickness (CST) before and after anti-VEGF injection were analyzed. Furthermore, changes in photoreceptor layer (PRL) thickness and outer retinal bands in the fovea after injection were evaluated. RESULTS: A total of 31 eyes with fibrovascular PED and 24 eyes with subretinal CNV were included. Following a relaxed treat-and-extend regimen with anti-VEGF agents, BCVA and CST were improved, and the PRL thickness was decreased significantly. There were no differences in BCVA, CST, changes in PRL thickness, or the status of outer retinal bands between the groups. However, the difference in the amount of decrease in PRL thickness between the two groups was increased at 2 years, and the slope tended to be steeper in the subretinal CNV group. CONCLUSIONS: Exudative age-related macular degeneration (AMD) with fibrovascular PED or subretinal CNV showed good visual/anatomic outcomes after anti-VEGF treatment, regardless of the CNV type. By 2 years, fibrovascular PED did not have an additional protective effect on the outer retina, compared with subretinal CNV over 2 years. Further follow-up study might be needed to conclude that fibrovascular PED has a protective effect on the surrounding photoreceptor area.

The effect of donor layer thickness on the power conversion efficiency of organic photovoltaic devices fabricated with a double small-molecular layer.

In organic photovoltaic (OPV) devices fabricated with a double small-molecular layer, the power conversion efficiency strongly depends on the thickness of the organic donor layer (here, copper phthalocyanine). In other words, the power conversion efficiency increases with the donor layer thickness up to a specific thickness ( approximately 12.7 nm) and then decreases beyond that thickness. This trend is associated with the light absorption and carrier transport resistance of the small-molecular donor layer, both of which strongly depend on the layer thickness. Experimental and calculated results showed that the short-circuit current due to light absorption increased with the donor layer thickness, while that due to current through the donor layer decreased with 1/R. Since the total short-circuit current is the product of the light absorption current and current through the donor layer, there is a trade-off, and the maximum power conversion efficiency occurs at a specific organic donor layer thickness (e.g. approximately 12.7 nm in this experiment).

The fabrication and characterization of organic light-emitting diodes using transparent single-crystal Si membranes.

For applications such as solar cells and displays, transparent single-crystal Si membranes were fabricated on a silicon-on-insulator (SOI) wafer. The SOI wafer included a buried layer of SiO2 and Si3N4 as an etch-stop layer. The etch-stop layer enabled fabrication of transparent single-crystal Si membranes with various thicknesses, and the thinning technology is described. For membranes with thicknesses of 18, 72 and 5000 nm, the respective optical transparent were 96.9%, 93.7% and 9% for R (red, lambda = 660 nm), 96.9%, 91.4% and 1% for G (green, lambda = 525 nm), and 97.0%, 93.2% and 0% for B (blue, lambda = 470 nm). Organic light-emitting diodes (OLEDs) were then fabricated on transparent single-crystal Si membranes with various top Si thicknesses. OLEDs fabricated on 18, 72 and 5000 nm thick membranes and operated at 6 V demonstrated a luminance of 1350, 443 and 27 cd m(-2) at the current densities of 148, 131 and 1.5 mA cm(-2), respectively.

OCT Angiography Findings of Tamoxifen Retinopathy: Similarity with Macular Telangiectasia Type 2.

PURPOSE: We aimed to describe the vascular changes in eyes associated with tamoxifen retinopathy using OCT angiography (OCTA) and to compare these changes with abnormalities in macular telangiectasia type 2 (MacTel 2) previously reported in the literature. DESIGN: Retrospective, observational study. PARTICIPANTS: Seventeen eyes with tamoxifen retinopathy and 17 eyes of age-matched healthy control participants. METHODS: The medical records of patients who visited the ophthalmology department with a history of taking tamoxifen were reviewed. Tamoxifen retinopathy was diagnosed based on typical spectral-domain (SD) OCT findings, such as intraretinal cavitation, photoreceptor disruption, or both. Multimodal imaging, particularly focused on OCTA, was analyzed. To compare vessel density in OCTA, age-matched normal control participants also were enrolled. MAIN OUTCOME MEASURES: Descriptive appraisal of the vascular abnormalities and objective quantification of vessel density associated with tamoxifen retinopathy. RESULTS: Among 292 patients who were screened, 26 were diagnosed with tamoxifen retinopathy. Of these, 17 eyes of 10 patients who were evaluated using OCTA were included. All patients were women, with a median patient age of 65.0 years. They were treated with tamoxifen as adjuvant endocrine therapy for breast cancer. All eyes showed intraretinal cavitation, and 8 eyes showed focal photoreceptor disruption as well, on OCT. On OCTA imaging, 14 eyes (82.4%) showed saccular capillary telangiectasia at the deep capillary plexus and 6 eyes (35.3%) showed right-angled vessels. Foveal vessel density of the superficial plexus was significantly lower in eyes with tamoxifen retinopathy than in control participants (P = 0.003). Crystalline deposits on fundus photographs (12 eyes [70.6%]) and increased autofluorescence on fundus autofluorescence (16 eyes [94.1%]) also were noted as characteristic findings of tamoxifen retinopathy. CONCLUSIONS: In addition to morphologic changes of tamoxifen retinopathy in SD OCT, its vascular changes on OCTA, such as telangiectatic vascular change at the deep capillary plexus and right-angled vessels, are similar to those observed in the early stages of MacTel 2.

Relationship Between Neutralizing Antibodies Against Adeno-Associated Virus in the Vitreous and Serum: Effects on Retinal Gene Therapy.

PURPOSE: We determine the prevalence of neutralizing antibodies (NAbs) to adeno-associated virus (AAV) in the vitreous humor and serum of patients with vitreoretinal diseases and investigate the relationship between NAb titers in the vitreous humor and serum. METHODS: We analyzed NAbs to AAV serotypes 2, 5, 8, and 9 via in vitro neutralization in the vitreous humor and serum from 32 patients requiring vitrectomy for vitreoretinal diseases. The blood-retinal barrier (BRB) was evaluated for integrity based on preoperative examinations, with vitreous hemorrhage (VH) on funduscopy or dye leakage on fluorescein angiography observed indicating disruption. RESULTS: NAb levels were much lower in the vitreous humor than in the serum regardless of serotype. Patients with VH had higher levels of NAbs in the vitreous humor than those without VH. The NAb ratio (ratio between NAb titers in the serum and vitreous humor) was much lower in patients with epiretinal membrane with than in those without leakage. A significantly lower NAb ratio was noticed in patients with than in those without BRB disruptions. CONCLUSIONS: The NAb ratio between levels in serum and vitreous humor varies according to the condition of the BRB. Therefore, in addition to measuring the serum NAb level, physicians should examine BRB integrity when planning retinal gene therapy. TRANSLATIONAL RELEVANCE: This study provides substantial basis for retinal gene therapy using AAVs and how maintenance of BRB integrity in target diseases should be considered.

Risk factors and outcomes of patients with ocular involvement of candidemia.

BACKGROUND: Ocular involvement of candidemia can result in serious complications, including vision loss. This study investigated the risk factors for ocular involvement in patients with candidemia and the outcomes of treatment. METHODS: Episodes of candidemia in hospitalized adults who underwent ophthalmic examinations within 2 weeks of candidemia onset between January 2014 and May 2017 were retrospectively reviewed. Their demographic characteristics, antifungal treatments, and visual outcomes were evaluated. RESULTS: During the study period, 438 adults were diagnosed with candidemia, with 275 (62.8%) undergoing ophthalmic examinations within 2 weeks. Of these 275 patients, 59 (21.5%) had fundoscopic abnormalities suggestive of ocular involvement, including 51 with chorioretinitis and eight with Candida endophthalmitis. Eleven patients were symptomatic. Persistent candidemia (adjusted odd ratio [aOR], 2.55; 95% confidence interval [CI], 1.29-5.08; P = 0.01), neutropenia during the preceding 2 weeks (aOR, 2.92; 95% CI, 1.14-7.53; P = 0.03), and C. albicans infection (aOR, 2.15; 95% CI, 1.09-4.24; P = 0.03) were independently associated with ocular involvement. Among the 24 patients with neutropenia, 41.7% had ocular involvements at the initial examination. Ophthalmologic examination even before the neutrophil recovery was positive in one-third of neutropenic patients. Out of the 37 patients in whom ocular outcomes after 6 weeks were available, 35 patients showed favorable or stable fundoscopic findings. Two patients had decreased visual acuity despite the stable fundoscopic finding. CONCLUSION: Neutropenia within two weeks of candidemia was a risk factor for ocular involvement. More than 80 percent of patients with ocular involvements were asymptomatic, emphasizing the importance of routine ophthalmic examinations. The median 6 weeks of systemic antifungal treatment resulted in favorable outcomes in 89.2% of patients.

An International Comparison of Baseline Characteristics of Patients Undergoing Initiation of Anti-VEGF Therapy for DME.

BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of vision loss worldwide. The object of this study is to compare global differences of baseline characteristics of patients undergoing initiation of anti-vascular endothelial growth factor (VEGF) therapy for DME. PATIENTS AND METHODS: This multicenter, cross-sectional study included diabetic patients with foveal-involving retinal edema secondary to DME as documented by fundus exam and optical coherence tomography who were undergoing initiation of intravitreal anti-VEGF drugs. Variables were collected to find possible risk factors and to create an epidemiological profile of DME patients undergoing initiation of anti-VEGF agents. RESULTS: Nine hundred two patients were selected. Mean age was 62.4 (±11) years, 49.7% were Caucasians, 57.6% were male, and 96% had type two diabetes with an average disease duration of 181.7 months ± 113 months. Of the patients included, 74.7% suffered from hypertension, 26.6% from cardiovascular disease, 12.1% from cerebrovascular disease, 12.8% from peripheral vascular disease, and 12.8% from renal insufficiency. Best-corrected visual acuity (BCVA) was 65 (±20) Early Treatment Diabetic Retinopathy Study letters, central subfield thickness was 364 (±162) µm, cube volume 11.1 ± 3.1 mm3, cube average thickness 328.8 µm ± 61 µm, and 63.9% had nonproliferative diabetic retinopathy. Comparison between U.S. versus international patients, and patients with BCVA 70 letters or less versus more than 70 letters were performed, significant differences were acknowledged, and risk factors were recognized. CONCLUSION: There were key differences in the epidemiologic profile between patients presenting with DME in the U.S. and internationally. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e300-e310.].

High efficient white organic light-emitting diodes using BCzVBi as blue fluorescent dopant.

Efficiency improvement and color optimization of white organic light-emitting diodes (WOLEDs) were achieved via employing blue host DPVBi doped with blue fluorescent, BCzVBi. The structure of high efficient WOLED device was composed of ITO/NPB/DPVBi:BCzVBi-6%/MADN:DCM2-0.5%/Bphen/Liq/Al. WOLED doped by blue fluorescent BCzVBi exhibits 6.19 cd/A of luminous efficiency and 15400 cd/m2 of maximum luminescence. It also performs 480 cd/m2 of luminance at 5.7 V and 15400 cd/m2 at 12.9 V with CIE(x,y) coordinates of (0.33, 0.32) and (0.32, 0.32), respectively. Hole carrier and energy transfer from DPVBi to BCzVBi are proposed to explain the observed phenomena.

Titanium dioxide thin films deposited by plasma enhanced atomic layer deposition for OLED passivation.

Plasma enhanced atomic layer deposition (PEALD) of titanium dioxide thin films was conducted using Tetrakis dimethylamino titanium (TDMATi) and an oxygen plasma on a polyethersulfon (PES) substrate at a deposition temperature of 90 degrees C. The effects of the induced plasma power on passivation properties were investigated according to film thickness. The growth rate of the titanium dioxide film was 0.8 A/cycle, and the water vapor transmission rate (WTVR) for a 80 nm titanium dioxide film was 0.023 g/m2 day. The passivation performance of the titanium dioxide film was investigated using an organic light-emitting diode (OLED). The coated OLED lifetime was 90 h, 15 times longer than that of an uncoated sample.

Energetics and Vibrational Signatures of Nucleobase Argyrophilic Interactions.

This study investigates the interactions of both purine (adenine and guanine) and pyrimidine (cytosine, thymine, and uracil) nucleobases with a pair of silver atoms (Ag2). Full geometry optimizations were performed on several structures of each nucleobase/Ag2 complex and the corresponding isolated monomers using the M06-2X density functional with a correlation consistent triple-ζ basis set augmented with diffuse functions on all atoms and a relativistic pseudopotential on Ag (aug-cc-pVTZ for H, C, N, and O and aug-cc-pVTZ-PP for Ag; denoted aVTZ). Harmonic vibrational frequency computations indicate that each optimized structure corresponds to a minimum on the M06-2X/aVTZ potential energy surface. Relative electronic energies for interactions between Ag2 and each nucleobase were compared to elucidate energetic differences between isomers. Further analysis of the changes in vibrational frequencies, infrared intensities, and Raman scattering activities reveals how different Ag2 binding sites might be differentiated spectroscopically. These results provide molecular-level insight into the interactions between nucleobases and silver, which may lead to better understanding and interpretation of surface-enhanced Raman spectroscopy experiments on nucleobases and related systems.