Vision, eye disease, and art: 2015 Keeler Lecture.

The purpose of this study was to examine normal vision and eye disease in relation to art. Ophthalmology cannot explain art, but vision is a tool for artists and its normal and abnormal characteristics may influence what an artist can do. The retina codes for contrast, and the impact of this is evident throughout art history from Asian brush painting, to Renaissance chiaroscuro, to Op Art. Art exists, and can portray day or night, only because of the way retina adjusts to light. Color processing is complex, but artists have exploited it to create shimmer (Seurat, Op Art), or to disconnect color from form (fauvists, expressionists, Andy Warhol). It is hazardous to diagnose eye disease from an artist's work, because artists have license to create as they wish. El Greco was not astigmatic; Monet was not myopic; Turner did not have cataracts. But when eye disease is documented, the effects can be analyzed. Color-blind artists limit their palette to ambers and blues, and avoid greens. Dense brown cataracts destroy color distinctions, and Monet's late canvases (before surgery) showed strange and intense uses of color. Degas had failing vision for 40 years, and his pastels grew coarser and coarser. He may have continued working because his blurred vision smoothed over the rough work. This paper can barely touch upon the complexity of either vision or art. However, it demonstrates some ways in which understanding vision and eye disease give insight into art, and thereby an appreciation of both art and ophthalmology.

How placement affects force and contact pressure between a volar plate of the distal radius and the flexor pollicus longus tendon: a biomechanical investigation.

Open reduction and internal fixation of a distal radius fracture can leave a volar plate in close proximity or touching the tendons of the wrist. This cadaveric study examines the how volar plate position changes contact pressure and force against the flexor pollicis longus (FPL) tendon in multiple wrist extension positions. This study suggests that moving the plate from an ideal position (distal edge at the watershed line) to a malposition (5 mm distal to the watershed line) significantly increased the force by 72.7% and contact pressure by 33.5% on the FPL. Multiple clinical case reports have described rupture of the flexor tendons associated with distally positioned plates or protruding screw heads, creating prominent or sharp edges. This study illustrates that in order to minimize contact pressure on the flexor tendons, plating distal to the watershed line should be avoided when possible.

Cementless fixation in total knee arthroplasty: down the boulevard of broken dreams - opposes.

In this study we present our experience with four generations of uncemented total knee arthroplasty (TKA) from Smith & Nephew: Tricon M, Tricon LS, Tricon II and Profix, focusing on the failure rates correlating with each design change. Beginning in 1984, 380 Tricon M, 435 Tricon LS, 305 Tricon 2 and 588 Profix were implanted by the senior author. The rate of revision for loosening was 1.1% for the Tricon M, 1.1% for the Tricon LS, 0.5% for the Tricon 2 with a HA coated tibial component, and 1.3% for the Profix TKA. No loosening of the femoral component was seen with the Tricon M, Tricon LS or Tricon 2, with no loosening seen of the tibial component with the Profix TKA. Regarding revision for wear, the incidence was 13.1% for the Tricon M, 6.6% for the Tricon LS, 2.3% for the Tricon 2, and 0% for the Profix. These results demonstrate that improvements in the design of uncemented components, including increased polyethylene thickness, improved polyethylene quality, and the introduction of hydroxyapatite coating, has improved the outcomes of uncemented TKA over time.

A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide/peptide/retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen.

BACKGROUND: Tretinoin is considered the benchmark prescription topical therapy for improving fine facial wrinkles, but skin tolerance issues can affect patient compliance. In contrast, cosmetic antiwrinkle products are well tolerated but are generally presumed to be less efficacious than tretinoin. OBJECTIVES: To compare the efficacy of a cosmetic moisturizer regimen vs. a prescription regimen with 0.02% tretinoin for improving the appearance of facial wrinkles. METHODS: An 8-week, randomized, parallel-group study was conducted in 196 women with moderate to moderately severe periorbital wrinkles. Following 2 weeks washout, subjects on the cosmetic regimen (n = 99) used a sun protection factor (SPF) 30 moisturizing lotion containing 5% niacinamide, peptides and antioxidants, a moisturizing cream containing niacinamide and peptides, and a targeted wrinkle product containing niacinamide, peptides and 0.3% retinyl propionate. Subjects on the prescription regimen (n = 97) used 0.02% tretinoin plus moisturizing SPF 30 sunscreen. Subject cohorts (n = 25) continued treatment for an additional 16 weeks. Changes in facial wrinkling were assessed by both expert grading and image analysis of digital images of subjects' faces and by self-assessment questionnaire. Product tolerance was assessed via clinical erythema and dryness grading, subject self-assessment, and determinations of skin barrier integrity (transepidermal water loss) and stratum corneum protein changes. RESULTS: The cosmetic regimen significantly improved wrinkle appearance after 8 weeks relative to tretinoin, with comparable benefits after 24 weeks. The cosmetic regimen was significantly better tolerated than tretinoin through 8 weeks by all measures. CONCLUSIONS: An appropriately designed cosmetic regimen can improve facial wrinkle appearance comparably with the benchmark prescription treatment, with improved tolerability.

Pulsed electron avalanche knife (PEAK) for intraocular surgery.

PURPOSE: To develop a better and more economical instrument for precise, tractionless, "cold" cutting during intraocular surgery. The use of highly localized electric fields rather than laser light as the means of tissue dissection was investigated. METHODS: A high electric field at the tip of a fine wire can, like lasers, initiate plasma formation. Micrometer-length plasma streamers are generated when an insulated 25 micron (microm) wire, exposed to physiological medium at one end, is subjected to nanosecond electrical pulses between 1 and 8 kV in magnitude. The explosive evaporation of water in the vicinity of these streamers cuts soft tissue without heat deposition into surrounding material (cold cutting). Streamers of plasma and the dynamics of water evaporation were imaged using an inverted microscope and fast flash photography. Cutting effectiveness was evaluated on both polyacrylamide gels, on different tissues from excised bovine eyes, and in vivo on rabbit retina. Standard histology techniques were used to examine the tissue. RESULTS: Electric pulses with energies between 150 and 670 microJ produced plasma streamers in saline between 10 and 200 microm in length. Application of electric discharges to dense (10%) polyacrylamide gels resulted in fracturing of the gel without ejection of bulk material. In both dense and softer (6%) gels, layer by layer shaving was possible with pulse energy rather than number of pulses as the determinant of ultimate cutting depth. The instrument made precise partial or full-thickness cuts of retina, iris, lens, and lens capsule without any evidence of thermal damage. Because different tissues require distinct energies for dissection, tissue-selective cutting on complex structures can be performed if the appropriate pulse energies are used; for example, retina can be dissected without damage to the major retinal vessels. CONCLUSIONS: This instrument, called the Pulsed Electron Avalanche Knife (PEAK), can quickly and precisely cut intraocular tissues without traction. The small delivery probe and modest cost make it promising for many ophthalmic applications, including retinal, cataract, and glaucoma surgery. In addition, the instrument may be useful in nonophthalmic procedures such as intravascular surgery and neurosurgery.

The dilemma of color deficiency and art.

No "major" painter is known to be color deficient. Are there truly no color deficient artists, or have they not been recognized? The historical literature cites criteria for recognizing color deficiency in artists, but they are hard to apply without knowing the intentions of an artist. The work and commentary of a color-deficient artist who works currently in Paris are presented as an example. He uses a limited palette of colors, based on advice from colleagues as much as his own perceptions, and he uses colors in ways that do not always fit with expectations for color deficiency. Biographies of earlier painters suggest that there were a few whose color sense was poor, but these painters used assistants to help. The color sense of others, such as the English landscape painter John Constable (1776-1837), has been questioned because of a preponderance of suspicious color, such as murky green. However, there are good reasons to doubt that Constable was color deficient. It is instructive to know how proven color deficiency has influenced an artist's style. When medical information is unavailable, the best advice for the diagnostically-inclined observer is just to enjoy the art.

The function of GPI-anchored proteins in T cell development, activation and regulation of homeostasis.

Many glycosylphosphatidyl-inositol-anchored proteins (GPI-AP) are expressed on T lymphocytes. Ligand or mAb-mediated aggregation of all GPI-AP tested to date results in the initiation of signal transduction pathways via the activation of src family protein tyrosine kinases. Src family kinases co-localise with GPI-AP in specialised sub-domains of the plasma membrane, referred to as detergent insoluble membrane microdomains (DIGS), which are thought to function as signalling platforms. GPI-AP may play a role in the regulation of T cell clonal expansion and effector functions at multiple levels, including the initiation of T cell activation through the antigen receptor complex, the regulation of ongoing responses supported by persisting antigen, as well as proliferative responses to the major T cell growth factor, IL-2. Evidence supporting the role of GPI-AP in the regulation of T cell development, activation and homeostasis is discussed, as well as insights provided by studies in humans and mice lacking GPI-AP.

HIV incidence among injection drug users in New York City, 1992-1997: evidence for a declining epidemic.

OBJECTIVES: We assessed recent (1992-1997) HIV incidence in the large HIV epidemic among injection drug users in New York City. METHODS: Data were compiled from 10 separate studies (N = 4979), including 6 cohort studies, 2 "repeat service user" studies, and 2 analyses of voluntary HIV testing and counseling services within drug treatment programs. RESULTS: In the 10 studies, 52 seroconversions were found in 6344 person-years at risk. The observed incidence rates among the 10 studies were all within a narrow range, from 0 per 100 person-years at risk to 2.96 per 100 person-years at risk. In 9 of the 10 studies, the observed incidence rate was less than 2 per 100 person-years at risk. The weighted average incidence rate was 0.7 per 100 person-years at risk. CONCLUSIONS: The recent incidence rate in New York City is quite low for a high-seroprevalence population of injection drug users. The very large HIV epidemic among injection drug users in New York City appears to have entered a "declining phase," characterized by low incidence and declining prevalence. The data suggest that very large high-seroprevalence HIV epidemics may be "reversed."

Sildenafil (Viagra) and ophthalmology.

Sildenafil citrate (Viagra) is a new oral medication that inhibits phosphodiesterase-5 (PDE5) in the corpus cavernosum to facilitate penile erection for the treatment of male impotence. The drug also has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients. Long-term retinal damage has not been reported, but long-term electroretinographic studies have not been performed. Sildenafil causes a mild lowering of blood pressure and is absolutely contraindicated in patients taking any form of nitrate medication. A number of cardiovascular deaths and retinal vascular events in patients taking sildenafil have been reported, but so far the rate of these complications does not exceed expectation for an elderly population. Ophthalmologists should alert patients to the ocular side effects and potential risks of this new drug until further clinical experience has been obtained.

The training of George K. Kambara, MD.

George K. Kambara has been a leader in ophthalmic education and practice on the West Coast. His choice of ophthalmology arose in part because of his experience running an eye, ear, nose, and throat clinic while interned as a Japanese American during World War II. His training took him from San Francisco, to the Tule Lake Relocation Center, to the Memphis Eye, Ear, Nose and Throat Hospital, to the University of Wisconsin, and eventually back to Los Angeles. He saw both sides of discrimination, as a Japanese American in California and as a "white" in the South. He was turned down for positions that he should have had based on his education, but he was also supported by many individuals who put aside public fears to help him. His story shows a triumph of the spirit, but is also a reminder of dark times that should not be forgotten.

Mechanisms of fluid accumulation in retinal edema.

This paper reviews the anatomic and physiologic conditions which predispose to fluid accumulation within the retina. Retinal edema has its inception in disease that causes a breakdown of the blood-retinal barrier in retinal capillaries and/or the retinal pigment epithelium (RPE). Edema develops not only because protein and fluid enter the extracellular space, but because the external limiting membrane and the convoluted extracellular pathway within the retina limit the clearance of albumin and other large osmotically-active molecules. These molecules bind water to cause edema. Recognition of edema clinically is complicated by the facts that angiographic markers (fluorescein and ICG) do not match albumin in size, and that clinical leakage does not always correlate closely with tissue swelling or functional loss. Active water transport across the RPE is efficient at removing subretinal water, but the flow resistance of the retina limits RPE access to the water of retinal edema. Consideration of the pathophysiology of retinal edema may aid in the development of better strategies for managing retinal edema.

Reexamination of human T cell lymphotropic virus (HTLV-I/II) prevalence.

In the United States, blood donors are being screened for infection with human T cell lymphotropic viruses I and II (HTLV-I/II) by serologic means, which detect antibodies to the structural proteins of these viruses. Because patients with mycosis fungoides (MF) usually do not have such antibodies even though their cells harbor HTLV-I Tax and/or pol proviral sequences, it was questioned whether the prevalence of HTLV infection among healthy blood donors may also be underestimated by current means of testing. To examine this possibility, a study on specimens of relatives of mycosis fungoides patients (MFR) was begun. In addition, to collect data more expeditiously, a cohort of former injection drug users (IDUs) was tested by routine serologic methods, as well as by PCR/Southern blot analysis for Tax, pol, and gag proviral sequences and Western blot analysis for antibodies to the Tax gene product. To date, 6/8 MFRs and 42/81 (51.8%) of HIV-negative IDUs proved to be positive for HTLV, whereas routine serology identified none of the MFR and only 18/81 (22.2%) of the IDUs. Among the latter test subjects, the incidence of HTLV-I also proved to be 10 times higher than expected. Therefore, it is likely that among healthy blood donors infection with HTLV-I/II is more prevalent than is currently assumed. Since Tax is the transforming sequence of HTLV-I/II, testing for Tax sequences and antibodies to its gene product may be desirable in blood transfusion and tissue donor facilities.

Determination of the true prevalence of infection with the human T-cell lymphotropic viruses (HTLV-I/II) may require a combination of biomolecular and serological analyses.

Infection with the human T-cell lymphotropic virus types I and II (HTLV-I/II) usually is determined by tests that detect antibodies to the viral structural proteins. However, recent studies revealed that patients with mycosis fungoides have proviral DNA sequences related to the HTLV transactivating-transforming gene tax, without having antibodies to the virus. These results raised the possibility that the prevalence of HTLV infection in the general population of the United States also may be underestimated. To reassess the prevalence of HTLV-I/II infection effectively, a population at increased risk for infection (i.e., a cohort of injection drug users [IDUs]) was studied. Paired sera and peripheral blood mononuclear cells (PBMCs) from 81 IDUs were subjected to testing by Western blot analysis for antibodies to the viral structural proteins gag and env and by polymerase chain reaction (PCR) Southern analysis to detect gag, pol and tax proviral DNA sequences. Western blot assays showed 1 of 81 IDUs to be positive for HTLV-I, 14 to be positive for antibodies to HTLV-II, and 3 to be HTLV-serotype indeterminate. When whole-cell lysates of PBMCs from these individuals were subjected to PCR and Southern analysis. 39 of 81 were found to have HTLV-related sequences. A total of nine IDUs were found to be infected with HTLV-I, a figure nearly 10 times higher than that estimated by serology alone. Bio-molecular analysis showed HTLV-II-specific proviral sequences in 21 IDUs. Three individuals were seropositive for HTLV-II but lacked PCR evidence of gag, pol and tax sequences. Thus, the overall prevalence of HTLV infection among this cohort was 59% (43 of 81) (i.e., more than twice the frequency predicted by serology, 18 of 81 or 22%). These results indicate that it may be necessary to incorporate biomolecular as well as serological methodologies to identify all persons infected with these retroviruses.

Methadone maintenance and other factors associated with intraindividual temporal trends in injection-drug use.

The objective of this study was to determine what sociodemographic, lifestyle, or drug-related characteristics predict temporal changes in self reported drug injection frequencies among HIV-seronegative injection-drug users (IDUs) who were being given HIV testing and risk reduction counseling. The 277 subjects were given 4-11 quarterly interviews including detailed history of drug use and other HIV risk factors, HIV risk reduction counseling, and venipuncture for HIV antibody testing. A regression slope of change over time in drug injection frequency was calculated for each subject, and categories were created of decreasing temporal slope, increasing slope, relapse (decrease initially, then increase), or no substantial change. Only 44% of subjects decreased their drug injection frequencies despite repetitive HIV testing and counseling. In multivariate logistic analyses, decreasing temporal trends were associated with consistent enrollment in methadone maintenance (p < .1), whereas increasing trends conversely were associated with inconsistent enrollment (p < .01) and also with an absence of crack use (p < .01). Relapses were significantly associated with needle sharing with multiple partners and a low frequency of smoking. The data suggest that methadone maintenance facilitates a positive response to HIV risk reduction counseling. However, the fact that only a minority of subjects displayed a decreasing temporal trend in drug injection frequencies emphasizes the need for improved therapeutic and counseling techniques.

Progress in identifying clinical relevance of inhibition, stimulation and measurements of poly ADP-ribosylation.

Our laboratory, in collaboration with Oxigene Inc, has been involved in identifying commercially feasible clinical applications of measurement or modulation of ADP-ribosylation as a core technology. For this purpose a pivotal regulatory role for ADP-ribosylation in the repair of DNA lesions leading to cytotoxic as well as mutagenic events has been hypothesized. A new class of DNA repair inhibitors, the N-substituted benzamides, has been identified which can react with radiation to produce reactive intermediates that oxidize thiol amino acids. Their proposed mechanisms of action are two-fold: ie they can interact with radiation: i) to directly enhance DNA damage; and ii) to react with thiols in the zinc finger DNA binding domain of poly ADP-ribosyl transferase to inhibit DNA repair and thereby increase DNA damage. Sensamide, a clinically relevant formulation of metoclopramide which is an N-substituted benzamide, has indicated enhancement of tumor response and survival in patients with inoperable squamous cell carcinoma of the lung when it was administered as a radiosensitizer in a phase I/II trial and compared to historical controls. A mechanism of endogenous regulation of human mononuclear leucocyte ADP-ribosylation has been identified to be HOCl/N-chloramine production via the oxidative burst of phagocytes. HOCl/N-chloramines are potent oxidants of thiol-containing proteins. Quantitative estimation of N-chloramine sensitive plasma thiols has been identified as an effective surrogate measure of leucocyte poly ADPRT.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for choroidal neovascularization in young patients: a case-control study.

A pair-matched, case-control design was used to study exposure to Histoplasma capsulatum and other environmental factors, and to determine various host characteristics including human leukocyte antigen (HLA) typings in 94 young patients with macular choroidal neovascularization (CNV) and in 94 controls with other eye diseases. Patients with two types of retinal patterns were studied: Type I, or those with CNV with one or no chorioretinal atrophic spots in the posterior pole or periphery (n = 51), and Type II, or those with CNV and 2 or more chorioretinal atrophic spots (n = 43). Our purpose was to explore whether these two variants of idiopathic CNV have different and distinguishable epidemiologies which may or may not be related to prior exposure to Histoplasma. We found that histoplasmin skin tests were negative in all but two Type I cases. The combination of the HLA-B7 and HLA-DR2 markers (but not either marker alone) was significantly increased in Type I cases. Among Type II cases, HLA-B7, HLA-DR2, HLA-DQ1, a positive histoplasmin skin test, myopic refractive error, prior residence in a histoplasmosis endemic area, occupations involving exposure to animals, and hypertension were all significantly increased. Histoplasmin skin test responses were positive in 18 Type II cases (45%). In the multivariate analysis, only DR2 and the combined presence of DQ1 and a positive histoplasmin skin test remained predictive of Type II disease. Our findings suggest that histoplasmin sensitivity is associated with some, but not all, cases of Type II disease. However, histoplasmin sensitivity appears to have no relationship to Type I disease. HLA factors may play a role in both disease types, possibly by producing a modified immune response to Histoplasma and/or other unidentified agents.

Iris melanoma in a ten-year-old boy with familial atypical mole-melanoma (FAM-M) syndrome.

A ten-year-old boy was referred with an enlarging amelanotic iris tumor and secondary glaucoma in the left eye. After excisional biopsy it proved histopathologically to be an iris melanoma. The patient also had multiple nevi on his trunk, scalp, and buttocks suggestive of familial atypical mole melanoma (FAM-M) syndrome and confirmed histopathologically. To the authors' knowledge, this is the first report of iris melanoma in association with FAM-M syndrome. The young age at tumor onset is suggestive of a predisposing condition such as FAM-M syndrome. The association of uveal melanoma with FAM-M syndrome is discussed.