José Sahel

Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse

Retinitis pigmentosa is an inherited degenerative disease of photoreceptors leading to blindness. A well-characterized model for this disease is provided by the retinal degeneration mouse, in which the gene for the rod cGMP phosphodiesterase is mutated, as in some affected human families. We report that D-cis-diltiazem, a calcium-channel blocker that also acts at light-sensitive cGMP-gated channels, rescued photoreceptors and preserved visual function in the retinal degeneration mouse. The long record of diltiazem prescription in cardiology should facilitate the design of clinical trials for some forms of retinitis pigmentosa.

Endoscopic transpapillary drainage of pancreatic pseudocysts

BACKGROUND Endoscopic therapy of pancreatic pseudocysts has been reported mainly in small series. METHODS The results of endoscopic transpapillary cyst drainage (ETCD) were evaluated prospectively in 30 patients with pancreatic pseudocysts. RESULTS There were 24 men and 6 women with an average age of 45 years (SD 16). Twenty-eight had chronic pancreatitis (25 with alcoholic pancreatitis). Transpapillary cystopancreatic stents, with the tip into the cyst cavity, were inserted in 12 patients. Pancreatic stents with the tip as close as possible from the cyst cavity were inserted in the remaining 18 patients. Ten patients underwent an additional endoscopic cystenterostomy. The average duration of stenting was 4.4 months (range 15 days to 12 months). Patients were followed up for 15 months (range 2 to 60 months). All pseudocysts communicated with the pancreatic ductal system. The size of the pseudocysts ranged from 15 to 120 mm (average 50 mm). Pseudocysts were mainly located in the head of the pancreas (17 cases). Four minor complications occurred. There were no deaths. Twenty-six patients had pseudocyst resolution by ETCD, but 7 ultimately required surgery, 3 for early recurrence and 4 for failure of initial therapy. CONCLUSION ETCD appears to be a safe and efficient modality for the drainage of pancreatic pseudocysts communicating with the pancreatic ductal system.

The Argus II epiretinal prosthesis system allows letter and word reading and long-term function in patients with profound vision loss

Background Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in outer retinal dystrophies. Ideal prostheses would offer stable, long-term retinal stimulation and reproducible spatial resolution in a portable form appropriate for daily life. Methods We report a prospective, internally controlled, multicentre trial of the Argus II system. Twenty-eight subjects with light perception vision received a retinal implant. Controlled, closed-group, forced-choice letter identification, and, open-choice two-, three- and four-letter word identification tests were carried out. Results The mean±SD percentage correct letter identification for 21 subjects tested were: letters L, T, E, J, F, H, I, U, 72.3±24.6% system on and 17.7±12.9% system off; letters A, Z, Q, V, N, W, O, C, D, M, 55.0±27.4% system on and 11.8%±10.7% system off, and letters K, R, G, X, B, Y, S, P, 51.7±28.9% system on and 15.3±7.4% system off. (p<0.001 for all groups). A subgroup of six subjects was able to consistently read letters of reduced size, the smallest measuring 0.9 cm (1.7°) at 30 cm, and four subjects correctly identify unrehearsed two-, three- and four-letter words. Average implant duration was 19.9 months. Conclusions Multiple blind subjects fitted with the Argus II system consistently identified letters and words using the device, indicating reproducible spatial resolution. This, in combination with stable, long-term function, represents significant progress in the evolution of artificial sight.

Case-control study of the risk factors for age related macular degeneration

AIM A case-control study was initiated to determine the risk factors for the development of age related macular degeneration (AMD). METHODS Study participants, who were all white, aged 50–85 years, and were recruited from private ophthalmology practices. Each practitioner enrolled patients with bilateral AMD, who were then matched with controls for sex and age. Environmental factors and systemic and ocular histories were screened. All patients had bilateral red-free fundus photographs and fluorescein angiography. Photographs were classified into pigment epithelium alterations, drusen, geographic atrophy, and exudative AMD. Statistical analysis included the identification of risk factors for AMD. A multivariate analysis was performed at the end of the study. Analysis included the entire study population and was carried out for each stage of AMD. RESULTS 1844 controls were compared with 1844 patients with AMD. Mean age was 71 years for controls and 72 for cases. Logistic regression identified six major risk factors for AMD (whole population): arterial hypertension (odds ratio (OR) =1.28), coronary disease (OR=1.31), hyperopia (OR=1.33), light coloured irises (OR=1.22), and lens opacities or previous cataract surgery (OR=1.55). The significance of vascular risk factors was increased for late stages of AMD, especially the atrophic forms (coronary disease, OR=3.19). CONCLUSIONS This large case-control study confirms some of the risk factors previously identified and may contribute to the determination of methods for prevention of AMD.

Chronic pancreatitis and inflammatory bowel disease: true or coincidental association?

OBJECTIVE:Several cases of pancreatitis have been described during the course of Crohns disease (CD) or ulcerative colitis (UC), but many of them were related to either biliary lithiasis or drug intake. We tried to evaluate the clinical and morphological features of so-called idiopathic pancreatitis associated with inflammatory bowel disease and to define their pathological characteristics.METHODS:Chronic idiopathic pancreatitis was diagnosed on the basis of abnormal pancreatograms suggestive of chronic pancreatitis associated with or without impaired exocrine pancreatic function, or pathological examination in patients undergoing pancreatic resection. We found 6 patients presenting with features of chronic idiopathic pancreatitis and UC and 2 patients with CD seen between 1981 and 1996 in three hospital centers of the south of France. A review of the literature has identified 6 cases of pancreatitis associated with UC and 14 cases of pancreatitis associated with CD based on the above criteria.RESULTS:Hyperamylasemia was not a sensitive test since it was present in 44% and 64% of patients with UC or CD. In UC, pancreatitis was a prior manifestation in 58% of patients. In contrast, the pancreatitis appeared after the onset of CD in 56% of the cases. In patients with UC, pancreatitis were associated with severe disease revealed by pancolitis (42%) and subsequent surgery. Bile duct involvement was more frequent in patients with UC than with CD (58%vs 12%) mostly in the absence of sclerosing cholangitis (16%vs 6%). Weight loss and pancreatic duct stenosis were also more frequent in UC than in CD (41%vs 12% and 50%vs 23%, respectively). Pathological specimens were analyzed in 5 patients and demonstrated the presence of inter- and intralobular fibrosis with marked acinar regression in 3 and the presence of granulomas in 2 patients, both with CD.CONCLUSIONS:Pancreatitis is a rare extraintestinal manifestation of inflammatory bowel disease. Chronic pancreatitis associated with UC differs from that observed in CD by the presence of more frequent bile duct involvement, weight loss, and pancreatic duct stenosis, possibly giving a pseudo-tumor pattern.

In vivo anterior segment imaging in the rat eye with high speed white light full-field optical coherence tomography

We present a new high speed full-field optical coherence tomography (OCT) instrument, the first full-field OCT system that is capable of in vivo ocular imaging. An isotropic resolution of ~ 1 mum is achieved thanks to the use of a xenon arc lamp source and relatively high numerical aperture microscope objectives in a Linnik-type interferometer. Full-field illumination allows the capture of two-dimensional en face images in parallel, using a fast CMOS camera as detector array. Each en face image is acquired in a 4 ms period, at a maximum repetition rate of 250 Hz. Detection sensitivity per en face image is 71 dB. Higher sensitivity can be achieved by image correlation and averaging, although frame rate is reduced. We present the first preliminary results of in vivo imaging in the anterior segment of the rat eye, which reveal some cellular features in the corneal layers.

Photoreceptor Transplants Increase Host Cone Survival in the Retinal Degeneration (rd) Mouse

Retinal transplants offer a potentially interesting approach to treating human retinal degenerations, but so far little quantitative data are available on possible beneficial effects. We isolated photoreceptor layers from normal-sighted mice and grafted them into the subretinal space of retinal degeneration (rd) mice lacking rod photoreceptors. At 2 weeks after surgery, the numbers of residual host cone photoreceptors outside the graft zone were quantified following specific labelling. Examination of operated retinas revealed highly significantly greater numbers of surviving cones (mean of 38% more at 2 weeks) within the central field compared to sham-operated paired control retinas (p < 0.01). These are the first quantified data indicating a trophic effect of transplanted photoreceptors upon host cone cells. As cone cells are responsible for high acuity and colour vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to understanding underlying interactions between retinal photoreceptors.

Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity

Although vigabatrin irreversibly constricts the visual field, it remains a potent therapy for infantile spasms and a third‐line drug for refractory epilepsies. In albino animals, this drug induces a reduction in retinal cell function, retinal disorganization, and cone photoreceptor damage. The objective of this study was to investigate the light dependence of the vigabatrin‐elicited retinal toxicity and to screen for molecules preventing this secondary effect of vigabatrin.

Rod-cone interactions: developmental and clinical significance.

During the last decade, numerous research reports have considerably improved our knowledge about the physiopathology of retinal degenerations. Three non-mutually exclusive general areas dealing with therapeutic approaches have been proposed; gene therapy, pharmacology and retinal transplantations. The first approach involving correction of the initial mutation, will need a great deal of time and further development before becoming a therapeutic tool in human clinical practice. The observation that cone photoreceptors, even those seemingly unaffected by any described anomaly, die secondarily to rod disappearance related to mutations expressed specifically in the latter, led us to study the interactions between these two photoreceptor populations to search for possible causal links between rod degeneration and cone death. These in vivo and in vitro studies suggest that paracrine interactions between both cell types exist and that rods are necessary for continued cone survival. Since the role of cones in visual perception is essential, pending the identification of the factors mediating these interactions underway, rod replacement by transplantation and/or neuroprotection by trophic factors or alternative pharmacological means appear as promising approaches for limiting secondary cone loss in currently untreatable blinding conditions.

Microglial changes occur without neural cell death in diabetic retinopathy

Very early neuroglial changes have been observed to precede major vascular changes in the retina of diabetic patients and animal models. We investigated the sequence of these neuroglial changes further, in mice with alloxan-induced diabetes. Diabetes was induced by a single injection of Alloxan into C57/Bl6 mice, which subsequently received daily insulin injections. Diabetic and control animals were weighed and their blood glucose levels were determined weekly. Electroretinographic recordings and scanner laser ophthalmoscope (SLO) examinations were carried out 15 days, one month and three months after the onset of diabetes. Diabetes induction was confirmed by the presence of glucose in the urine, a tripling of blood glucose level, weight loss and an increase in glycated haemoglobin levels. Three months after diabetes onset, the electroretinogram b/a wave amplitude ratio was decreased at the highest light intensities and oscillatory potentials were delayed. The retinal fundus and vessels remained unchanged. No cell apoptosis was detected in vertical and horizontal sections of the retina by TUNEL or immunocytochemistry for the active caspase 3. No increase in GFAP-immunostaining indicative of a glial reaction was observed in Müller glial cells. By contrast, changes in the morphology of microglial cells were observed, with marked shortening of the dendrites. Thus, the microglial reaction occurs very early in progression to diabetic retinopathy, at about the same time as early electroretinographic modifications. The absence of apoptotic cells, contrasting with previous results in mice with streptozotocin-induced diabetes, is consistent with insulin neuroprotection.