Retinal vascular occlusion after vitrectomy with retrobulbar anesthesia-observational case series and survey of literature

BACKGROUND: Severe postoperative loss of vision has been occasionally reported as a rare complication of retrobulbar anesthesia, and several possible causes have been proposed in the literature. In this work, our own and other investigators' experiences with these complications are surveyed with a view to identifying its pathophysiology. PATIENTS: This observational case series refers to six patients who presented during a 3-month period with occlusion of either the central artery itself (n = 3) or a branch thereof (n = 3) 2-14 days after uneventful vitreoretinal surgery following retrobulbar anesthesia with a commercial preparation of mepivacaine (1% Scandicain®, Astra Chemicals, Sweden) containing methyl- and propyl parahydroxybenzoate as preservatives. RESULTS: Three of the patients carried risk factors, which were medically controlled. In three individuals, vasoocclusion was observed after a second vitreoretinal intervention, which was performed 3-12 months after uneventful primary surgery. Good visual recovery was observed in only one instance. CONCLUSIONS: In patients who were anesthetized with preservative-free mepivacaine, no vasoocclusion occurred. In individuals who were anesthetized with mepivacaine containing the preservatives methyl- and propyl parahydroxybenzoate, a tenfold increase in the incidence of eyes requiring re-operation was documented, with a 2- to 14-day lapse in the onset of vasoocclusion. These findings reveal a possible implication of preservatives contained in the local anesthetic solution for the vasoocclusive events. Due to this potential hazard, the use of preservative-free preparations of local anesthesia in ocular surgery is emphasized in order to prevent this sight-threatening complication.

Microfluidic wound-healing assay to assess the regenerative effect of HGF on wounded alveolar epithelium

We present a microfluidic epithelial wound-healing assay that allows characterization of the effect of hepatocyte growth factor (HGF) on the regeneration of alveolar epithelium using a flow-focusing technique to create a regular wound in the epithelial monolayer. The phenotype of the epithelial cell was characterized using immunostaining for tight junction (TJ) proteins and transmission electron micrographs (TEMs) of cells cultured in the microfluidic system, a technique that is reported here for the first time. We demonstrate that alveolar epithelial cells cultured in a microfluidic environment preserve their phenotype before and after wounding. In addition, we report a wound-healing benefit induced by addition of HGF to the cell culture medium (19.2 vs. 13.5 μm h(-1) healing rate).

Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut

Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.

Association of macular pigment density with plasma ω-3 fatty acids: the PIMAVOSA study

To assess the correlation between macular pigment optical density and plasma levels of lutein, zeaxanthin, and fatty acids, especially omega-3 polyunsaturated fatty acids (PUFAs).

Retinal crystals in type 2 idiopathic macular telangiectasia

To characterize the phenotype and investigate the associations of intraretinal crystalline deposits in a large cohort with type 2 idiopathic macular telangiectasia (MacTel).

Retinal thickness in Parkinson's disease

BACKGROUND: Visual symptoms are common in Parkinson's disease with studies consistently demonstrating reductions in visual acuity, contrast sensitivity, colour and motion perception as well as alterations in electroretinogram latencies and amplitudes. Optical coherence tomography can examine retinal structure non-invasively and retinal thinning has been suggested as a potential biomarker for neurodegeneration in Parkinson's disease. Our aim was to examine the retinal thickness of a cohort of Parkinson's disease subjects (and age-matched controls) to establish the practical utility of optical coherence tomography in a representative older Parkinson's disease group. METHODS: Fifty-one established Parkinson's disease subjects and 25 healthy controls were subjected to ophthalmological assessment and optical coherence tomography (Zeiss Stratus 3000™) of macular thickness and volume and retinal nerve fibre thickness around the optic nerve head. Twenty four percent of control and 20% of Parkinson's disease subjects were excluded from final analysis due to co-morbid ocular pathology. Further data was excluded either due to poor tolerability of optical coherence tomography or poor quality scans. RESULTS: Despite a reduction in both visual acuity and contrast sensitivity in the residual evaluable Parkinson's disease cohort, we did not detect any differences between the two study groups for any measures of retinal thickness, in contrast to previously published work. CONCLUSIONS: In addition to technical problems inherent in the evaluation, the lack of difference between Parkinson's disease and healthy control subjects suggests longitudinal studies, employing newer techniques, will be required to define the role of optical coherence tomography as a potential diagnostic biomarker.

The airway epithelium: soldier in the fight against respiratory viruses

The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions. It initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. The interaction between respiratory viruses and airway epithelial cells results in production of antiviral substances, including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, and also in production of cytokines and chemokines, which recruit inflammatory cells and influence adaptive immunity. These defense mechanisms usually result in rapid virus clearance. However, respiratory viruses elaborate strategies to evade antiviral mechanisms and immune responses. They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms. In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones. Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.

Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells

It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the spatio-temporal patterns of expression of three such cytokines, IL-1β, TNFα and IL-6, in a validated rat model of experimental glaucoma. First, only weak evidence was found for increased expression of IL-1β and TNFα following induction of ocular hypertension. Second, and much more striking, was that robust evidence was uncovered showing IL-6 to be synthesised by injured retinal ganglion cells following elevation of intraocular pressure and transported in an orthograde fashion along the nerve, accumulating at sites of axonal disruption in the optic nerve head. Verification that IL-6 represents a novel marker of disrupted axonal transport in this model was obtained by performing double labelling immunofluorescence with recognised markers of fast axonal transport. The stimulus for IL-6 synthesis and axonal transport during experimental glaucoma arose from axonal injury rather than ocular hypertension, as the response was identical after optic nerve crush and bilateral occlusion of the carotid arteries, each of which is independent of elevated intraocular pressure. Moreover, the response of IL-6 was not a generalised feature of the gp130 family of cytokines, as it was not mimicked by another family member, ciliary neurotrophic factor. Finally, further study suggested that IL-6 may be an early part of the endogenous regenerative response as the cytokine colocalised with growth-associated membrane phosphoprotein-43 in some putative regenerating axons, and potently stimulated neuritogenesis in retinal ganglion cells in culture, an effect that was additive to that of ciliary neurotrophic factor. These data comprise clear evidence that IL-6 is actively involved in the attempt of injured retinal ganglion cells to regenerate their axons.

Effects of daunorubicin, mitomycin C, azathioprine and cyclosporin A on human retinal pigmented epithelial, corneal endothelial and conjunctival cell lines

BACKGROUND: We wished to investigate the toxicity of four immunosuppressant and antimetabolic drugs, which are known to influence postoperative wound healing, on three different human ocular cell lines. METHODS: Acute toxicity to cyclosporin A, azathioprine, mitomicyn C and daunorubicin was assessed in Chang cells by monitoring their uptake of propidium iodide during a 3-h period. Chronic toxicity was assessed by monitoring the proliferation and viability of subconfluent cultures of Chang cells, human corneal endothelial cells (HCECs) and retinal pigmented epithelial (RPE) cells after continuous exposure to the drugs for 7 days. RESULTS: Acute toxicity testing revealed no obvious effects. However, the chronic toxicity tests disclosed a narrow concentration range over which cell proliferation decreased dramatically but calcein metabolism was sustained. Although the three lines reacted similarly to each agent, HCECs were the most vulnerable to daunorubicin and mitomycin. At a daunorubicin concentration of 0.05 microg/ml, a 75% decrease in calcein metabolism (P < 0.001) and a > or = 95% cell loss (P < 0.001) were observed. At a mitomycin concentration of 0.01 mug/ml, cell density decreased by 61% (P < 0.001) without a change in calcein metabolism, but at 0.1 microg/ml, the latter parameter decreased to 12% (P = 0.00014). At this concentration the proliferation of Chang and RPE cells decreased by more than 50%, whilst calcein metabolism was largely sustained. Cyclosporin inhibited cell proliferation moderately at lower concentrations (< 5 microg/ml; P=0.05) and substantially at higher ones, with a corresponding decline in calcein metabolism. Azathioprine induced a profound decrease in both parameters at concentrations above 5 microg/ml. CONCLUSION: Daunorubicin, cyclosporin and azathioprine could be used to inhibit excessive intraocular scarring after glaucoma and vitreoretinal surgery without overly reducing cell viability. The attributes of immunosuppressants lie in their combined antiproliferative and immunomodulatory effects.

Galectin-3 modulates T cell activity and is reduced in the inflamed intestinal epithelium in IBD

BACKGROUND: Galectins are involved at different stages in inflammation. Galectin-3, although mostly described as proinflammatory, can also act as an immunomodulator by inducing apoptosis in T cells. The present study aims to determine galectin-3 expression in the normal and inflamed intestinal mucosa and to define its role in T cell activity. MATERIALS AND METHODS: Galectin-3 was detected by quantitative polymerase chain reaction with total RNA from endoscopic biopsies and by immunohistochemistry. Biopsies and peripheral blood mononuclear cells (PBMC) were stimulated in vitro and were used to assess the functional consequences of inhibition or exogenous addition of galectin-3. RESULTS: Galectin-3 is expressed at comparable levels in controls and inflammatory bowel disease (IBD) patients in remission. In the normal mucosa, galectin-3 protein was mainly observed in differentiated enterocytes, preferentially at the basolateral side. However, galectin-3 was significantly downregulated in inflamed biopsies from IBD patients. Ex vivo stimulation of uninflamed biopsies with tumor necrosis factor led to similar galectin-3 messenger RNA downregulation as in vivo. When peripheral blood mononuclear cells (PBMC) were analyzed, galectin-3 was mainly produced by monocytes. Upon mitogen stimulation, we observed increased proliferation and decreased activation-induced cell death of peripheral blood T cells in the presence of galectin-3-specific small interfering RNA. In contrast, exogenous addition of recombinant galectin-3 led to reduced proliferation of mitogen-stimulated peripheral blood T cells. CONCLUSIONS: Our results suggest that downregulation of epithelial galectin-3 in the inflamed mucosa reflects a normal immunological consequence, whereas under noninflammatory conditions, its constitutive expression may help to prevent inappropriate immune responses against commensal bacteria or food compounds. Therefore, galectin-3 may prove valuable for manipulating disease activity.

CD40 ligation protects bronchial epithelium against oxidant-induced caspase-independent cell death

CD40 and its ligand regulate pleiotropic biological responses, including cell proliferation, differentiation, and apoptosis. In many inflammatory lung diseases, tissue damage by environmental or endogenous oxidants plays a major role in disease pathogenesis. As the epithelial barrier is a major target for these oxidants, we postulated that CD40, the expression of which is increased in asthma, plays a role in the regulation of apoptosis of bronchial epithelial cells exposed to oxidants. Using 16HBE 14o- cells exposed to oxidant stress, we found that ligation of CD40 (induced by G28-5 monoclonal antibodies) enhanced cell survival and increased the number of cells in G2/M (interphase between DNA synthesis and mitosis) of the cell cycle. This was associated with NF-kappaB and activator protein-1 activation and increased expression of the inhibitor of apoptosis, c-IAP1. However, oxidant stress-induced apoptosis was found to be caspase- and calpain-independent implicating CD40 ligation as a regulator of caspase-independent cell death. This was confirmed by the demonstration that CD40 ligation prevented mitochondrial release and nuclear translocation of apoptosis inducing factor. In conclusion, we demonstrate a novel role for CD40 as a regulator of epithelial cell survival against oxidant stress. Furthermore, we have identified, for the first time, an endogenous inhibitory pathway of caspase-independent cell death.