Glucocorticoids induce retinal toxicity through mechanisms mainly associated with paraptosis.

PURPOSE: Corticosteroids have recorded beneficial clinical effects and are widely used in medicine. In ophthalmology, besides their treatment benefits, side effects, including ocular toxicity have been observed especially when intraocular delivery is used. The mechanism of these toxic events remains, however, poorly understood. In our present study, we investigated the mechanisms and potential pathways of corticosteroid-induced retinal cell death. METHODS: Rats were sacrificed 24 h and 8 days after an intravitreous injection of 1 microl (40 microg) of Kenacort Retard. The eyes were processed for ultra structure analysis and detection of activated caspase-3, cytochrome-C, apoptosis-inducing factor (AIF), LEI-L-Dnase II, terminal transferase dUTP nick end labeling (TUNEL), and microtubule-associated protein 1-light chain 3 (MAP-LC3). In vitro, rat retinal pigment epithelial cells (RPE), retinal Müller glial cells (RMG) and human ARPE-19 cells were treated with triamcinolone acetonide (TA) or other glucocorticoids. Cell viability was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5 phenyltetrazolium bromide test (MTT) assay and cell counts. Nuclei staining, TUNEL assay, annexin-V binding, activated caspase-3 and lactate dehydrogenase (LDH) production characterized cell death. Localization of cytochrome-C, AIF, LEI-and L-Dnase II, and staining with MAP-LC3 or monodansylcadaverine were also carried out. Finally, ARPE-19 cells transfected with AIP-1/Alix were exposed to TA. RESULTS: In vitro incubation of retinal cell in the presence of corticosteroids induced a specific and dose-dependent reduction of cell viability. These toxic events were not associated with the anti-inflammatory activity of these compounds but depended on the hydro solubility of their formulation. Before cell death, extensive cytoplasmic vacuolization was observed in the retinal pigment epithelial (RPE) cells in vivo and in vitro. The cells however, did not show known caspase-dependent or caspase-independent apoptotic reactions. These intracellular vacuoles were negative for MAP-LC3 but some stained positive for monodansylcadaverine. Furthermore, over expression of AIP-1/Alix inhibited RPE cell death. CONCLUSIONS: These observations suggest that corticosteroid-induced retinal cell death may be carried out mainly through a paraptosis pathway.

AUTOIMMUNE PANCREATITIS

Autoimmune Pancreatitis (AIP) is a new nosological entity that was first reported by Sarles et al. in 1961 and then named by Yoshida et al. in 1995 in Japan. It was then ignored by many Western researchers and now, in the last decade; it appears to have been recognized worldwide. AIP is a distinct form a chronic pancreatitis with an immune mediated fibroinflammatory process that has unique histopathologic features that makes it distinguishable from other forms of pancreatitis. Moreover, AIP is the only type of pancreatitis that responds to steroid administration. The Honolulu consensus document that has recently been published by Chari et al. described the histopathologic and clinical subtypes of AIP. Indeed, it appears that there are two forms of AIP, with different prevalence in Europe and Asia and distinct clinical profiles. The first subtype, the most common type in Asia, has recently been named Lymphoplasmocytic sclerosing pancreatitis (LPSP) or type I AIP because of its histological features and its association with elevated IgG serum levels and various autoantibodies. The second one is called idiopathic duct centric pancreatitis, IDCP, or type II AIP, that barely exists in Japan, but more accounted in Caucasian people. IDCP is recognized by its particular histology that is a granulocytic epithelial lesion (GEL) which makes some people call it AIP with GEL. Still nowadays, the diagnosis of AIP is a challenge. AIP can only be definitively diagnosed by histological examination. The main differential diagnosis of AIP is, except chronic pancreatitis, pancreatic cancer. That explains why there are still some unnecessary resections. Several groups have proposed diagnostic criteria for AIP as in Japan, Korea, Germany, Italy and the United States. Thus, it is important to find an international consensus. Above all, it is important to find new criteria as specific markers in the serum and the pancreatic tissues, for example using proteomics, to be able to diagnosis both types of AIP, and distinguish AIP from pancreatic cancer in order to avoid surgical resection in patients with AIP. The aim of this project is to review all relevant studies about AIP and to document all the available diagnostic tools.

Low-frequency transcranial magnetic stimulation over left dorsal premotor cortex improves the dynamic control of visuospatially cued actions.

Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.