Heat shock proteins: new keys to the development of cytoprotective therapies.

All cells, from bacterial to human, have a common, intricate response to stress that protects them from injury. Heat shock proteins (Hsps), also known as stress proteins and molecular chaperones, play a central role in protecting cellular homeostatic processes from environmental and physiologic insult by preserving the structure of normal proteins and repairing or removing damaged ones. An understanding of the interplay between Hsps and cell stress tolerance will provide new tools for treatment and drug design that maximise preservation or restoration of health. For example, the increased vulnerability of tissues to injury in some conditions, such as ageing, diabetes mellitus and menopause, or with the use of certain drugs,, such as some antihypertensive medications, is associated with an impaired Hsp response. Additionally, diseases that are associated with tissue oxidation, free radical formation, disorders of protein folding, or inflammation, may be improved therapeutically by elevated expression of Hsps. The accumulation of Hsps, whether induced physiologically, pharmacologically, genetically, or by direct administration of the proteins, is known to protect the organism from a great variety of pathological conditions, including myocardial infarction, stroke, sepsis, viral infection, trauma, neurodegenerative diseases, retinal damage, congestive heart failure, arthritis, sunburn, colitis, gastric ulcer, diabetic complications and transplanted organ failure. Conversely, lowering Hsps in cancer tissues can amplify the effectiveness of chemo- or radiotherapy. Treatments and agents that induce Hsps include hyperthermia, heavy metals (zinc and tin), salicylates, dexamethasone, cocaine, nicotine, alcohol, alpha-adrenergic agonists, PPAR-gamma agonists, bimoclomol, geldanamycin, geranylgeranylacetone and cyclopentenone prostanoids. Compounds that suppress Hsps include quercetin (a bioflavinoid), 15-deoxyspergualin (an immunosuppressive agent) and retinoic acid. Researchers who are cognisant of the Hsp-related effects of these and other agents will be able to use them to develop new therapeutic paradigms.

Expression of vascular endothelial growth factor in uveal melanoma and its correlation with metastasis.

AIMS: To evaluate the expression of vascular endothelial growth factor (VEGF) in uveal melanomas and correlate its presence with tumour characteristics and systemic metastasis. METHODS: 47 cases of ciliochoroidal melanoma enucleated between 1983 and 1993 were retrieved from the pathology archives at the University of Western Ontario. Paraffin sections stained with haematoxylin and eosin, periodic acid Schiff, and periodic acid Schiff without haematoxylin after bleaching of melanin were examined. The expression of VEGF protein was examined by an immunoalkaline phosphatase method following antigen retrieval, using an antibody to VEGF and vector red as the chromogen. The intensity of VEGF immunoreactivity was graded on a scale of 0-7 and correlated with tumour cell type, tumour size, presence or absence of necrosis, pigmentation, mitotic activity, microvascular density, and microvascular pattern. RESULTS: VEGF immunoreactivity was present in 44/47 tumours (94%): the intensity was graded as very weak (1-2) in 29/47 (62%) and as weak or greater in 15/47 (32%). VEGF was also found in the ciliary epithelium, smooth muscle of the ciliary body and iris, retinal ganglion cells, inner photoreceptor segments, and the retinal pigment epithelium. Follow up data were available in 43/47 patients (91.5%), with a median follow up time of 10 years. 16/43 (37%) patients developed metastases. VEGF expression in melanoma was linked to the presence of tumour necrosis and the degree of pigmentation but no statistically significant relation with microvascular pattern, tumour size, or microvascular density was found. There was no statistically significant correlation between VEGF expression and metastasis. CONCLUSIONS: Most ciliochoroidal melanomas express VEGF and expression is correlated with the presence of necrosis but not with the occurrence of systemic metastasis or tumour angiogenesis.

A "thinking-in-action" approach to teaching clinical judgment: a classroom innovation for acute care advanced practice nurses.

The complexity of the evolving advanced practice nurse (APN) role demands new teaching strategies. Based on the challenges that clinicians face daily, we have developed a teaching-learning strategy that addresses five central issues: (a) learning to perceive or identify relevant clinical problems; (b) learning to address the limits of formalism by situating clinical problem solving according to the most relevant goals and intents; (c) learning to reason in transition about the particular clinical situation; (d) learning the ethical skill of problem engagement and interpersonal involvement; and (e) learning to take a stand as a responsible agent by making clinical judgments, acting on them, and advocating for the patient/family. Although these five central issues are typically excluded from classic academic approaches, they are addressed in the "Thinking-in-Action" approach. This teaching-learning strategy offers a different way of teaching clinical judgment that closely resembles the way in which expert nurses actually think and reason in patient situations as they unfold.

Effects of Valsalva's manoeuvre on intraocular pressure.

We examined the effects of breath holding against a closed glottis (Valsalva's manoeuvre) on intraocular pressure (IOP) in four groups of volunteer subjects: 37 healthy young control subjects, 10 patients with chronic open-angle glaucoma, 11 age-matched control subjects and 8 glaucoma suspects. IOP was recorded by one person using a Digilab 30R/T Pneuma-Tonometer. Chart recordings of the IOP were measured independently by a second investigator. Recordings were taken before, during and 5 minutes after the seated subject exhaled into an aneroid manometer to a pressure of 25 to 35 cm H2O. There was marked variability in the individual responses to Valsalva's manoeuvre in all four groups, with substantial increases (to +9.5 mm Hg) and decreases (to -4.0 mm Hg) in IOP seen. The mean change in IOP during Valsalva's manoeuvre was a small, statistically insignificant decrease in all four groups. The mean change in IOP following Valsalva's manoeuvre was a larger, but still clinically small, decrease. The clinician should be aware of the individual variability in IOP changes with Valsalva's manoeuvre.

Trans-scleral neodymium: YAG retinal photocoagulation in rabbit eyes.

To assess the ability of trans-scleral application of the continuous-wave neodymium: YAG laser to produce retinal ablation with reproducible chorioretinal scars, retinal photocoagulation with the YAG laser was done in four Dutch-belted rabbits (eight eyes). Sharply defined, reproducible lesions were produced that were identical to those found following conventional treatment with the argon laser. At 0.2 J there was destruction of the outer retinal layers with sparing of the inner retinal layers. At 3.0 J full-thickness retinal reorganization was noted; however, even at this energy setting there was minimal histologic evidence of scleral damage. Focused laser energy produced distinctly more retinal destruction and obliteration of the retinal pigment epithelium than unfocused energy. The results suggest that trans-scleral photocoagulation with the YAG laser may be possible and would be particularly applicable in situations in which media opacities preclude visualization of the retina.

Triple agent immunosuppression in serpiginous choroiditis.

Serpiginous choroidopathy is a progressive choroidal inflammatory disorder that typically has a variable saltatory course. Response to steroids is uncertain. By using azathioprine, cyclosporine, and prednisone in combination, the authors have observed rapid remission of active disease in five patients. Remissions have been maintained for periods up to 18 months. Because of the synergistic effects of this combination, doses could rapidly be reduced to maintenance levels without reactivation. Disease in two patients recurred immediately after discontinuation of low-dose therapy but was arrested when therapy resumed. Triple agent immunosuppressive therapy is well tolerated and appears to be effective.

Cataract extraction in uveitis patients.

Cataracts are known to develop at an accelerated rate in many forms of uveitis. Until recently, cataract surgery in such eyes was regarded as a hazardous procedure that yielded unpredictable and often discouraging results. Recent evidence from a number of reports suggests that newer surgical techniques and careful medical management allow a significant number of patients with uveitis to undergo cataract extraction successfully. Intraocular lens implantation using in-the-bag posterior chamber lens technique has been successful in selected cases. Careful patient selection, coupled with the use of an appropriate surgical technique, appear to be of major importance. Herein we review the current literature on cataract extraction in uveitis and provide guidelines for patient and technique selection based on the type of inflammation present. The management of common surgical problems and complications is discussed, as is the role of the intraocular lens. Specific surgical techniques useful in the management of eyes with cataract and uveitis are discussed.