Patenting medical and surgical techniques: an ethical-legal analysis.

Considerable controversy has recently arisen regarding the patenting of medical and surgical processes in the United States. One such patent, viz. for a "chevron" incision used in ophthalmologic surgery, has especially occasioned heated response including a major, condemnatory ethics policy statement from the American Medical Association as well as federal legislation denying patent protection for most uses of a patented medical or surgical procedure. This article identifies and discusses the major legal, ethical and public policy considerations offered by proponents and opponents of such patents. The existing literature divides up into those who favor such patents essentially without qualification, and those who condemn and wish to outlaw them. We advance a compromise position where administrative and legislative action is called for to provide more specific guidelines regarding the patentability of such processes by the Patent and Trademark Office. Our position, in sum, will be that too much is at stake in this complicated area for either the blanket prohibition, or wholesale, uncritical acceptance, of the patenting of medical and surgical processes or techniques.

Antioxidant enzymes in human tears.

Minimally stimulated tear samples collected from human subjects were assayed for the major antioxidant enzymes: superoxide dismutase, catalase and glutathione peroxidase. No catalase or glutathione peroxidase activity was detected. However, human tear film does contain the CuZn superoxide dismutase (103 +/- 32 ng/mg soluble protein), which is inactivated by hydrogen peroxide (0.2 mM). These data indicate that the tear film has the enzyme generally required for control of inflammatory conditions but is lacking the usual physiological defense systems against the toxicity of hydrogen peroxide. Concern has been raised as to the safety of contact lens disinfectant solutions containing hydrogen peroxide. These results indicate that the tear film is lacking the enzyme systems to provide significant protection to the cornea, to the tear film itself, or to the SOD of the tear film from the oxidant action of hydrogen peroxide.

Kinetics of corneal epithelial maintenance and graft loss. A population balance model.

We use a population balance model to study the mechanism and the rate of centripetal migration of epithelial cells, renewal of the corneal epithelial population by the cell derived from (progeny of) the limbal stem cells and the kinetics of the replacement of the donor corneal epithelium. The epithelial mass is constant under the normal circumstances and therefore the rate of cellular entry due to centripetal motion and mitosis into any epithelial volume must equal the cell loss from the same volume. The magnitude of the centripetal velocity and the rate of replacement of the donor tissue following keratoplasty are shown to depend only on the following directly quantifiable factors--the difference in the mitotic rates of the corneal and limbal epithelia and the radii of these two epithelia. The a priori model predictions are found to be in very good agreement with the observed centripetal velocities and the rate of corneal graft replacement. The model provides an independent support for the hypothesis that the stem cells for the corneal epithelium are located in the limbus and are responsible for a slow replenishment of the corneal epithelial cell. The model suggests some factors that diminish the centripetal supply of cells and thus provides insights into the pathogenesis of persistent corneal defects and delayed reepithelialization of defects and grafts. The model is suitable for interpreting and quantitatively correlating the influence of some epithelial alterations and drugs on the centripetal supply of epithelial cells.

Teaching the informed consent process to residents.

We believe the focus and emphasis of this committee on informed consent is unique, and that the development of an informed consent teaching process for residents will focus on the moral and ethical issues regarding informed consent. Even more important, we believe we will emphasize the patient care aspects of informed consent and also teach residents their responsibilities for long-term patient care with regard to patients' satisfaction and understanding of their disease process.

Stellate iron lines in the corneal epithelium after radial keratotomy.

Biomicroscopic examinations of the corneal epithelium of 54 patients who had consecutive radial keratotomy operations in the National Eye Institute Prospective Evaluation of Radial Keratotomy (PERK) study showed that abnormal stellate epithelial iron lines had appeared at the junction of the middle and inferior thirds of the cornea in 13 of 16 eyes (81%) examined six months after surgery, in 43 of 50 eyes (86%) examined 12 months after surgery, and in seven of nine eyes (78%) examined 24 months after surgery. The density and pattern of the deposits varied from a faint tan horizontal iron line studded with small branches to a dense yellow-brown deposit with eight radiating arms that extended between all of the incisions. Analysis of the configuration of the iron line and the central keratometric readings 12 months after surgery showed that the greater the reduction in the central keratometric measurement postoperatively, the more prominent the iron line. We attribute the occurrence and variation of the stellate epithelial iron line to irregularities in the surface of the cornea present in the first year after radial keratotomy.

The effect of age on corneal and lens superoxide dismutase.

The enzymatic activity of copper-zinc superoxide dismutase within the cornea and lens of the juvenile (1 week) and adult (26 week) rat has been measured relative to both total soluble protein and immunoreactive protein. Enzymatic activity of corneal superoxide dismutase, localized in the epithelium and endothelium, remains constant with age relative to total soluble protein and the ratio of catalytically active enzyme to immunoreactive enzyme is near unity indicating that the superoxide dismutase present is enzymatically active. Likewise, in the juvenile rat, the majority of lens superoxide dismutase, which is located in the capsule epithelium, is enzymatically active. However, in the adult rat a large portion of the enzyme present is catalytically inactive. The enzymatic activity also decreases relative to total soluble protein with age in both the rat and the rabbit lens. This decrease in protection against toxic radicals and/or the accumulation of enzymatically defective enzyme may be contributing factors to age related lens disorders.

Dynamics of ocular surface pH.

We studied ocular surface pH in 161 subjects. The mean pH for 133 normal volunteers was 7 . 11, SD 1 . 5. We found that older women had a more alkaline pH than other subjects, that the pH shifted from acid to alkaline during the day, that one hour of eyelid closure caused an acid shift in pH, and that pH recovered to baseline values within 40 minutes after acid drop instillation. We explored the mechanism of pH regulation, and we believe that pH changes could affect contact lens toleration, drug effectiveness, and clinical signs in disease processes.

Localization of corneal superoxide dismutase by biochemical and histocytochemical techniques.

Superoxide dismutase activity is found in the cornea of rats, dogs, rabbits and humans. A superoxide dismutase identical to the Cu-Zn enzyme is identified by biochemical and immunochemical methods in the corneal epithelium and endothelium in relative high abundance (90-100 U mg-1 protein). The enzyme quantities detected by radioimmune assay and bioactivity assay are similar, giving evidence that the enzyme present is biologically functional. Immunohistochemical techniques demonstrate the association of the enzyme with the cytoplasm of these layers. Soluble protein extracts of corneal stroma exhibit weak apparent superoxide dismutase activity which is found to be mainly due to copper associated with serum albumin.

Treatment of essential blepharospasm. I. Comparison of facial nerve avulsion and eyebrow-eyelid muscle stripping procedure.

Benign essential blepharospasm is an incurable disease for which many treatment modalities have been suggested. The two surgical procedures that have been used most commonly are avulsion of the facial nerve and stripping of the protractor muscles of the eyelid and brow. We compare two matched series of 22 patients; one group underwent facial nerve avulsion ("Reynold's" procedure), and the other underwent "muscle stripping" ("Anderson's" procedure). We noted the number of procedures required for the patient to obtain a functional visual result and the side effects produced. Additional surgical procedures required by patients undergoing facial nerve avulsion were additional facial nerve avulsion, repair of ectropion, and correction of dermatochalasis and brow droop. Additional procedures required in patients who had muscle stripping were excision of lower lid orbicular fibers or residual brow fibers. The Reynold group required 16 additional procedures (38 separate procedures) to obtain functional results, as opposed to the four additional procedures (26 separate procedures) required in the Anderson group. Two patients in the Reynold group who needed surgery have not yet undergone it at this writing. If they did, that would boost the total number of procedures to 40. Secondary procedures are needed 4.5 times more often with the Reynold procedure than with the Anderson procedure. The patient's subjective response to and acceptance of the procedure are much greater for the Anderson procedure.

Corneal endothelium: a modified method for cultivation.

A modified method for establishing cultures of rabbit corneal cells is described. The new technique utilized a Lucite disc in combination with a Tygon ring for growth of pure cell cultures and was compared with an explant method for growing cells. Each method provided adequate cell cultures for biochemical or ultrastructure studies of rabbit corneal cells, but the ring and disc method described here allowed the isolation of specific cell types without the interference of stromal cell contamination.

Signs of essential blepharospasm: a motion-picture analysis.

Motion pictures of 15 patients with essential blepharospasm were studied. Previously unrecognized signs indicated multiple cranial nerve involvement. These signs include impersistence of gaze, lid retraction, tongue thrust, head tilts, head jerks, vertical gaze spasms, and asymmetry. The sugns were also observed in a patient with bilateral blepharospasm who had a history of Bell's palsy suggesting facial nerve injury as a possible factor in blepharospasm. The presence of these signs can be explained by known neural pathways, but the site, or sites, of the lesion remains obscure. These signs may be important in assessing severity and in treatment evaluation.

Effects of antibiotics on the in vitro rabbit corneal endothelium.

The effects of ten antibiotics and two preservatives on the rabbit corneal endothelium were studied by in vitro perfusion. Dose-related effects on corneal thickness were seen with certain antibiotics. No correlation was found between structure, origin, or bacterial sensitivity of the antibiotics and their effect on corneal transplants. Five distinct morphological changes were observed: two were transient and only one was specific. Although clinical dose correlation was not intended, further investigation is needed on erythromycin, bacitracin, chloramphenicol, penicillin, oxacillin, and cephalothin.

Pilocarpine toxicity. Effects on the rabbit corneal endothelium.

The effects of pilocarpine on the healthy rabbit corneal endothelium were studied by in vitro perfusion, photography, and electron microscopy. The toxicity of endothelial cells to pilocarpine was doserelated. Photography showed shrinkage of cells exposed to pilocarpine. The most striking ultrastructure changes were margination of nuclear heterochromatin and cytoplasmic vacuolation.