Progressive multifocal leukoencephalopathy following chemotherapy for lung cancer.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus infection and with a frequent lethal outcome. PML usually occurs in immunocompromised subjects, such as HIV-positive individuals, as well as in other conditions characterized by depletion of cellular immunity, including hematological malignancies, autoimmune diseases, and immunomodulatory therapies. We describe the case of a 76-year-old man affected by advanced non-small cell lung cancer who developed PML after six cycles of carboplatin/gemcitabine therapy, during which a transitory leucopenia developed. The patient deceased a few months after the onset of the symptoms. Chemotherapy appears to be uncommon, but definite condition associated to PML.

Association of increased CCL5 and CXCL7 chemokine expression with neutrophil activation in severe stable COPD.

BACKGROUND: Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease. OBJECTIVES: To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I-IV) compared with age-matched control subjects, smokers with normal lung function and never smokers. METHODS: The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB). RESULTS: The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2-15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD. CONCLUSION: The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.

T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.

There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22(+) and IL-23(+) immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A(+) and IL-22(+) immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22(+) cells correlated significantly with the number of both CD4(+) and CD8(+) cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.

Long-term histological and electrophysiological results of an inactive epiretinal electrode array implantation in dogs.

PURPOSE: Short-term pattern electrical stimulation of the retina via multielectrode arrays in humans blind from photoreceptor loss has shown that ambulatory vision and limited character recognition is possible. To develop an implantable retinal prosthesis that would provide useful vision, these results need to be sustained over a prolonged period of retinal electrical stimulation. As a first step toward this goal, the biocompatibility and the feasibility of surgically implanting an electrically inactive electrode array onto the retinal surface was tested. METHODS: A 5 x 5 electrode array (25 platinum disc-shaped electrodes in a silicone matrix) was implanted onto the retinal surface using retinal tacks in each of the 4 mixed-breed sighted dogs. Color fundus photography, fluorescein angiography, electroretinography, and visual evoked potentials were obtained preoperatively, at 1-week intervals for 2 weeks postoperatively, then at 2-week intervals up to 2 months postoperatively, and thereafter at 1-month intervals. One dog was killed at 2 months after implantation and a second dog after 3 months of implantation. Histologic evaluation of the retinas was performed. The remaining two dogs continue to be followed beyond 6 months after the implantation surgery. RESULTS: No retinal detachment, infection, or uncontrolled intraocular bleeding occurred in any of the animals. Retinal tacks and the retinal array remained firmly affixed to the retina throughout the follow-up period. Hyperpigmentation of the retinal pigment epithelium was observed only around the site of retinal tack insertion. No fibrous encapsulation of the implant or intraocular inflammation was visible. A- and b-wave amplitudes of the electroretinogram were depressed at the first postoperative week testing but recovered over the ensuing 1 week and were not statistically different from the normal unoperated fellow eye throughout the postoperative period. N1 and P1 wave amplitudes of the visual evoked potentials were not significantly different from the normal fellow eyes at any of the postoperative test intervals. Fluorescein angiography showed that the entire retina including the area under the electrode array remained well perfused. Similarly, histologic evaluation revealed near total preservation of the retina underlying the electrode array. CONCLUSIONS: Implantation of an electrode array on the epiretinal side (i.e., side closest to the ganglion cell layer) is surgically feasible, with insignificant damage to the underlying retina. The platinum and silicone arrays as well as the metal tacks are biocompatible. With the success of implanting an electrically inactive device onto the retinal surface for prolonged periods, the effects of long-term retinal electrical stimulation are now ready to be tested as the next step toward developing a prototype retinal prosthesis for human use.

Clinical and histopathologic features of canine oxygen-induced proliferative retinopathy.

PURPOSE: In previous studies the morphologic features of the acute vaso-obliterative and vasoproliferative stages of oxygen-induced retinopathy (OIR) were quantified and described in the dog model of retinopathy of prematurity (ROP). In the present study the sequelae of these events were examined using fluorescein angiography and histologic, enzyme, and immunohistochemical techniques. METHODS: Thirty newborn animals were exposed to 95% to 100% oxygen for 4 days and returned to room air until they were 22 to 45 days of age. Before death some animals were anesthetized, and fluorescein angiography was performed. Retina and vitreous from some animals were processed for adenosine diphosphatase (ADPase) flat-embedding. In other cases, eyes were prepared for full-thickness eyewall sectioning or frozen for histochemical analysis. RESULTS: Fluorescein angiography, funduscopic examination, and ADPase preparations showed dilated and tortuous retinal vessels, pigmentary changes, incomplete vascularization of peripheral retina, vitreous hemorrhage, and persistence of massive intravitreal neovascularization. Full-thickness eyewall sections showed tractional retinal folds, tented intravitreal vascularized membranes, and vitreous synchysis. Immunohistochemical analysis showed inner retinal astrogliosis. Enzyme histochemistry showed high alpha glycerophosphate dehydrogenase activity in poorly differentiated neovascular formations and low activity in formations with mature pericytes and endothelial cells. CONCLUSIONS: End-stage OIR in the neonatal dog shares many features with the chronic human disease. These results provide additional support for the use of this model in experimental studies of ROP.

Increased sensitivity of the non-human primate eye to microwave radiation following ophthalmic drug pretreatment.

Previous studies in our laboratory have established that pulsed microwaves at 2.45 GHz and 10 mW/cm2 are associated with production of corneal endothelial lesions and with disruption of the blood-aqueous barrier in the non-human primate eye. In the study reported here we examined ocular damage in monkeys (M. mulatta and M. fascicularis) following topical treatment with one of two ophthalmic drugs (timolol maleate and pilocarpine) that preceded exposure to pulsed microwaves. Anesthetized monkeys were sham exposed or exposed to pulsed, 2.45 GHz microwaves (10 microseconds, 100 pps) at average power densities of 0.2, 1, 5, 10, or 15 mW/cm2 4 h a day for 3 consecutive days (respective SARs were 0.052, 0.26, 1.3, 2.6, and 3.9 W/kg). Immediately before microwave exposure, one or both eyes were treated topically with one drop of 0.5% timolol maleate or of 2% pilocarpine. Following administration of a drug, we observed a significant reduction in the power-density threshold (from 10 to 1 mW/cm2) for induction of corneal endothelial lesions and for increased vascular permeability of the iris. Diagnostic procedures (in vivo specular microscopy and fluorescein iris angiography) were performed following each exposure protocol. In addition, increased vascular permeability was confirmed with horseradish peroxidase tracer techniques. Although we did not measure intraocular temperatures in experimental animals, the results suggest that a mechanism other than significant heating of the eye is involved. Our data indicate that pulsed microwaves at an average SAR of 0.26 W/kg, if administered after pretreatment with ophthalmic drugs, can produce significant ocular effects in the anesthetized primate.

A primate model of macular cyst.

Perfluoropropane (C3F8) was injected into nine eyes of six cynomolgus monkeys. In all nine eyes, macular changes consistent with the development of a macular cyst were noted within 3 months after injection. On fluorescein angiography, there was no evidence of retinal vascular leakage associated with the macular cysts. Histopathologic evaluation of six eyes demonstrated microcystic changes throughout the perifoveal inner nuclear layer. These coalesced into larger cystic spaces in the outer plexiform layer of the central macula. These macular changes are previously unreported in patients or monkeys undergoing intravitreal injection of expansile gases. This model for macular cysts may be helpful in evaluating the pathogenesis and role of interventional strategies in patients with cystoid macular edema.

A primate model of anterior segment ischemia after strabismus surgery. The role of the conjunctival circulation.

Fornix conjunctival incisions in strabismus surgery may provide partial protection against anterior segment ischemia by preserving the perilimbal conjunctival-Tenon's circulation, which is disrupted with limbal conjunctival incisions. Six adult cynomolgus monkeys underwent tenotomies of three or four rectus muscles by making limbal conjunctival incisions in one eye and fornix incisions in the other. Iris fluorescein angiography and slit-lamp biomicroscopy were used to monitor changes. The eyes that had limbal incisions exhibited more severe anterior segment ischemic changes than the eyes that had fornix incisions in every instance of four rectus muscle surgery.

Neodymium:YAG laser iridotomy in the cynomolgus monkey.

The histologic effects of various Neodymium:YAG laser energy levels were evaluated after iridotomy formation in cynomolgus monkey eyes. Scanning election microscopy of the corneal endothelium above the treated areas revealed no significant cell loss or pleomorphism when compared to the adjacent untreated areas. Light and phase contrast microscopy demonstrated closure of the iridotomies in most cases by a bridge of iris pigment epithelium. In several specimens, stromal tissue and pigment laden cells were present over the attenuated iris pigment epithelium. There were four lens opacities with rupture of the anterior lens capsule and anterior epithelial cell hyperplasia in one. No damage was apparent in the trabecular meshwork or retina with light microscopy or fluorescein angiography.

High-resolution photography of the retinal nerve fiber layer.

Abnormalities in the appearance of the retinal nerve fiber layer can indicate the presence of optic nerve atrophy, but a major problem has been the difficulty of visualizing the nerve fiber layer in some individuals. By selectively illuminating the white nerve fiber layer in comparison with the red retinal pigment epithelium and choroidal background, red-free light increases the visibility of the nerve fiber layer. Compared with the standard red-free photographic technique, a 560-nm short-pass cut-off filter, used with extended-range, high-resolution, extremely fine-grain film (Kodak No. 2415 Technical Pan film), considerably enhanced the ability to resolve nerve fiber bundles.

Histologic studies of angle structures after laser iridotomy in primates.

Each of nine eyes of five cynomolgus monkeys had argon laser peripheral iridotomies performed to investigate the histologic effects on the trabecular meshwork. The laser technique was the same as is used in human eyes. With laser iridotomy, particulate debris was released into the anterior chamber and rapidly accumulated in the angle. The densest initial deposit was in the inferior juxtacanalicular trabecular meshwork. Histologically, pigment was located both extracellularly and within giant vacuoles of the endothelium and Schlemm's canal and intracellularly within trabecular endothelial cells. This finding indicates that this pigment is removed from the anterior chamber both by bulk aqueous flow and by phagocytosis. One year after iridotomy, only a slightly increased pigmentation of the angle was still present. No permanent ultrastructural damage to the angle was detected.

Corneal endothelial changes after argon-laser iridotomy and panretinal photocoagulation.

We performed argon-laser peripheral iridotomies on the right eyes of eight cynomolgus monkeys and administered panretinal scatter photocoagulation to the left eyes of the same monkeys. Both eyes of each monkey were photographed and studied with a slit lamp, pachymetry, and direct and indirect specular microscopy. After follow-up periods of 0 to 31 days, the monkeys were killed and the enucleated eyes studied by light and scanning electron microscopy. Scanning microscopy were deposits showed that the changes observed by specular microscopy were deposits on the endothelium. Only minimal damage occurred and there were no significant changes in endothelial cell density after either treatment.