Vogt-Koyanagi-Harada disease: inquiry into the genesis of a disease name in the historical context of Switzerland and Japan

Purpose: To delineate the historical steps associated with the genesis of the name and the definition of Vogt-Koyanagi-Harada (VKH) disease. Methods: A bibliographical review of the major publications that were relevant to the original development of the name of the clinical entity known today as Vogt-Koyanagi-Harada disease, in the historical context of the early 20th century. Results: Three distinct time periods can be considered to be important in terms of providing a historical perspective on VKH disease. Given that the cutaneous manifestations of VKH disease are so characteristic, these could not have been missed even before the actual clinical entity of VKH was recognized in the early 20th century. Indeed, several authors, including the Arabic doctor Mohammad-al-Ghâfiqî in the 12th century as well as Jacobi, Nettelship and Tay in the 19th century, described poliosis, neuralgias and hearing disorders. Many of these cases were probably due to sympathetic ophthalmia, but some were clearly VKH cases. The second phase is characterized by the surge of articles that appeared early in the 20th century that defined the disease more precisely. A number of these authors subsequently became associated with the disease name, the first being Alfred Vogt from Switzerland, followed by Japanese researchers. Yoshizo Koyanagi was in fact not the first Japanese author to describe the disease; this honor goes to the first Japanese Professor of Ophthalmology at the University of Tokyo, Dr. Jujiro Komoto, who published in a German language journal, Klinische Monatsblätter für Augenheilkunde in 1911. Yoshizo Koyanagi published his first report in the Nippon Ganka Gakkai Zasshi 3 years later, in 1914, but it was a much later article, one published in 1929, that definitively associated his name with the disease. In this review article, Koyanagi reported 16 cases, of which six were his own cases, that beautifully illustrate the natural course of the disease. In this same time period, Einosuke Harada, in an article published in Nippon Ganka Gakkai Zasshi in 1926 that was based on several case studies, comprehensively described a syndrome that included (1) a prodromal phase of malaise and meningeal irritation; (2) bilateral uveitis of diverse intensity; (3) bilateral retinal detachments spontaneously resolving; (4) integumentary changes; (5) lymphocytosis of the spinal fluid; (6) dysacousia. It is now accepted that Vogt-Koyanagi disease and the syndrome described by Harada are one entity with a diverse clinical spectrum bearing the universally accepted name of Vogt-Koyanagi-Harada disease. The third phase and most recent phase is characterized by the rapid progress made in terms of knowledge of the physiopathology of the disease, primarily due to the development of immunological methods. The evidence accumulated to date clearly points towards an autoimmune Th1 disease directed against proteins associated with choroidal melanin. Other analytical techniques, such as indocyanine green angiography, have enabled researchers to monitor more closely the primary lesional process at the level of the choroid, and standardized diagnostic criteria have been generated in the recent past. Conclusion: Those who earn scientific merit in clinical medicine are the ones who are able to visualize an overview based on the synthesis of ‘new' medical facts that have been made available, usually reported singly by several, unassociated authors concomitantly. This is certainly the case for Yoshizo Koyanagi and Einosuke Harada. Conversely, Alfred Vogt was primarily lucky in that he encountered and subsequently precisely described the first case in the literatur

Logical Operation Based Literature Association with Genes and its application, PosMed.

PosMed prioritizes candidate genes for positional cloning by employing our original database search engine GRASE, which uses an inferential process similar to an artificial neural network comprising documental neurons (or 'documentrons') that represent each document contained in databases such as MEDLINE and OMIM (Yoshida, _et al_. 2009, Makita, _et al_. 2009). PosMed immediately ranks the candidate genes by connecting phenotypic keywords to the genes through connections representing gene–gene interactions other biological relationships, such as metabolite–gene, mutant mouse–gene, drug–gene, disease–gene, and protein–protein interactions, ortholog data, and gene–literature connections.

To make proper relationships between genes and literature, we manually curate queries, which are defined by logical operation rules, against MEDLINE. For example, to detect a set of MEDLINE documents for the AT1G03880 gene in _A. thaliana_, we applied the following logical query: (‘AT1G03880’ OR ‘CRU2’ OR ‘CRB’ OR ‘CRUCIFERIN 2' OR ‘CRUCIFERIN B’) AND (‘Arabidopsis’) NOT (‘chloroplast RNA binding’). Curators refined these queries in mouse, rice and _A. thaliana_. For human and rat genes, we use mouse curation results via ortholog genes in PosMed.

PosMed is available at "http://omicspace.riken.jp/PosMed":http://omicspace.riken.jp/PosMed

References:
Yoshida Y, et al. _Nucleic Acids Res_. 37(Web Server issue):W147-52. 2009. 
Makita Y, et al. _Plant Cell Physiol_. 2009 Jul;50(7):1249-59.
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Indocyanine green angiography findings in initial acute pretreatment Vogt-Koyanagi-Harada disease in Japanese patients

Purpose: Indocyanine green angiography (IA) is a highly sensitive method to evaluate choroidal inflammatory lesions. We present standardized IA findings of initial acute Vogt-Koyanagi-Harada (VKH) disease in Japanese patients before therapeutical intervention. Methods: Medical records of patients with VKH disease at Tokyo Medical and Dental University Hospital and Miyata Eye Hospital were retrospectively analyzed. We analyzed six IA signs: choroidal perfusion inhomogeneity, early hyperfluorescent stromal vessels, hypofluorescent dark dots (HDDs), fuzzy or lost pattern of large stromal vessels, disc hyperfluorescence, and diffuse late choroidal hyperfluorescence. Results: Ten patients from the two hospitals were studied. The most constant findings present in all eyes were early hyperfluorescent stromal vessels, HDDs, and either fuzzy or lost pattern of large stromal vessels. Disc hyperfluorescence was present in 18 eyes. Choroidal perfusion inhomogeneity was seen in six patients, and diffuse late choroidal hyperfluorescence was seen to a certain degree in all eyes. Conclusions: Four of the analyzed signs, including early hyperfluorescent stromal vessels, HDDs, fuzzy or lost pattern of large stromal vessels, and disc hyperfluorescence were consistent findings in Japanese VKH patients. Because the primary lesion is situated in the choroid, IA is the method of choice to monitor disease activity in VKH diseas

Suboptimal therapy controls clinically apparent disease but not subclinical progression of Vogt-Koyanagi-Harada disease

Purpose To evaluate clinical and angiographic differences in patients with Vogt-Koyanagi-Harada (VKH) disease during the early 4-month treatment phase with high- or medium-dose systemic corticosteroid therapy. Methods VKH patients treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland (n=4), or the Department of Ophthalmology, Tokyo Medical and Dental University, Tokyo, Japan (n=5), underwent a pre-treatment indocyanine green angiography (ICGA) and a follow-up ICGA four months after treatment began. Lausanne patients received high-dose, systemic corticosteroid therapy, with or without immunosuppressive therapy. Tokyo patients received medium-dose systemic corticosteroid therapy that included 3days of intravenous pulse methylprednisolone. ICGA signs including choroidal stromal vessel hyperfluorescence and leakage, hypofluorescent dark dots (HDD), fuzzy vascular pattern of large stromal vessels and disc hyperfluorescence were retrospectively compared. Results The pre-treatment ICGA demonstrated that each of the nine patients had choroidal inflammatory foci, as indicated by HDD. At 4-month follow-up, clinical and fluorescein findings had improved almost equally in both groups. HDD had resolved in the Lausanne group but persisted in the Tokyo group. Sunset glow fundus occurred in three of the Tokyo patients and none of the Lausanne patients. Conclusions Submaximal doses of inflammation suppressive therapy are sufficient to suppress clinically apparent disease but not the underlying lesion process. This explains the propensity for sunset glow fundus in seemingly controlled diseas

Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism

A 43-year-old woman with drug-related blepharospasm was followed up for 22 months. She had undergone etizolam treatment for 19 years for indefinite complaints. We examined her cerebral glucose metabolism 5 times (between days 149 and 688 since presentation), using positron emission tomography, and identified regions of interest in the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides. The severity of the blepharospasm was evaluated by PET scanning using the Wakakura classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal controls. The thalamic glucose metabolism in our patient was significantly increased on days 149, 212, and 688. The severity of the blepharospasm was positively correlated with the thalamic glucose metabolism, suggesting that the severity of blepharospasms reflects thalamic activity

SUV39H1 interacts with HTLV-1 Tax and abrogates Tax transactivation of HTLV-1 LTR

BACKGROUND: Tax is the oncoprotein of HTLV-1 which deregulates signal transduction pathways, transcription of genes and cell cycle regulation of host cells. Transacting function of Tax is mainly mediated by its protein-protein interactions with host cellular factors. As to Tax-mediated regulation of gene expression of HTLV-1 and cellular genes, Tax was shown to regulate histone acetylation through its physical interaction with histone acetylases and deacetylases. However, functional interaction of Tax with histone methyltransferases (HMTase) has not been studied. Here we examined the ability of Tax to interact with a histone methyltransferase SUV39H1 that methylates histone H3 lysine 9 (H3K9) and represses transcription of genes, and studied the functional effects of the interaction on HTLV-1 gene expression. RESULTS: Tax was shown to interact with SUV39H1 in vitro, and the interaction is largely dependent on the C-terminal half of SUV39H1 containing the SET domain. Tax does not affect the methyltransferase activity of SUV39H1 but tethers SUV39H1 to a Tax containing complex in the nuclei. In reporter gene assays, co-expression of SUV39H1 represses Tax transactivation of HTLV-1 LTR promoter activity, which was dependent on the methyltransferase activity of SUV39H1. Furthermore, SUV39H1 expression is induced along with Tax in JPX9 cells. Chromatin immunoprecipitation (ChIP) analysis shows localization of SUV39H1 on the LTR after Tax induction, but not in the absence of Tax induction, in JPX9 transformants retaining HTLV-1-Luc plasmid. Immunoblotting shows higher levels of SUV39H1 expression in HTLV-1 transformed and latently infected cell lines. CONCLUSION: Our study revealed for the first time the interaction between Tax and SUV39H1 and apparent tethering of SUV39H1 by Tax to the HTLV-1 LTR. It is speculated that Tax-mediated tethering of SUV39H1 to the LTR and induction of the repressive histone modification on the chromatin through H3 K9 methylation may be the basis for the dose-dependent repression of Tax transactivation of LTR by SUV39H1. Tax-induced SUV39H1 expression, Tax-SUV39H1 interaction and tethering to the LTR may provide a support for an idea that the above sequence of events may form a negative feedback loop that self-limits HTLV-1 viral gene expression in infected cells

Work-up, diagnosis and management of acute Vogt-Koyanagi-Harada disease: A case of acute myopization with granulomatous uveitis

Purpose: In its typical form and when seen at onset, Vogt-Koyanagi-Harada (VKH) is characterized by easily recognizable signs that allow diagnosis without difficulty. In cases that do not have acute onset, that are seen at a later stage or that do not show the complete set of signs, appraisal is more difficult and diagnosis may cause difficulties. We present here a case of bilateral granulomatous uveitis compatible with VKH disease in order to allow several experts to give their opinion on the most appropriate manner to confirm or reject the diagnosis and their approach to the management of the case. Case presentation: A 17-year-old female patient consulted her ophthalmologist for blurred vision OU following an episode of a flu-like disease with malaise, fever and headaches. A bilateral anterior granulomatous uveitis with a right papillitis was diagnosed and the patient presented with a bilateral acute myopization. Fluorescein angiography showed right disc hyperfluorescence with late leakage and slight left disc hyperfluorescence. The patient was given a course of one week of peroral corticosteroid therapy followed by an intramuscular injection of Bentelan® twice weekly. In the absence of significant improvement the patient was sent sixweeks later to a specialized center where a complete work-up was performed. Expert opinion: The diagnostic work-up, investigational tests, and differential diagnosis to confirm or reject the diagnosis of VKH as well as the management of the case will be described by the expert