IL-12 conditioning improves retrovirally mediated transduction efficiency of CD8+ T cells.

The ability to genetically modify T cells is a critical component to many immunotherapeutic strategies and research studies. However, the success of these approaches is often limited by transduction efficiency. As retroviral vectors require cell division for integration, transduction efficiency is dependent on the appropriate activation and culture conditions for T cells. Naive CD8(+) T cells, which are quiescent, must be first activated to induce cell division to allow genetic modification. To optimize this process, we activated mouse T cells with a panel of different cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-12, IL-15 and IL-23, known to act on T cells. After activation, cytokines were removed, and activated T cells were retrovirally transduced. We found that IL-12 preconditioning of mouse T cells greatly enhanced transduction efficiency, while preserving function and expansion potential. We also observed a similar transduction-enhancing effect of IL-12 preconditioning on human T cells. These findings provide a simple method to improve the transduction efficiencies of CD8(+) T cells.

The scalp topography of the human visually evoked subcortical potential.

Stimulus and analysis parameters have been adjusted to provide optimum conditions for producing and recording the early components of flash visual evoked potentials. A visual evoked subcortical potential (VESP) of mean latency P23-N28-P34 has been recorded in 86% of subjects. The triphasic wave was maximal at an electrode position slightly posterior to the Rolandic/sylvian fissure and topographically separate from the lid electroretinogram and the visual evoked cortical potential. Monocular stimulation shows bilateral reduction of the amplitude of the VESP, indicating that the wave is independent of the retina and optic nerve and must be arising from a postchiasmal site.

The visually evoked subcortical potential: is related to the electroretinogram?

The visually evoked subcortical potential (VESP) of mean latencies P21-N28-P36 has previously been recorded at an electrode site around the mastoid process. An initial topographical study of the potential indicated that it was independent of the electroretinogram (ERG), and monocular stimulation showed bilateral reduction, which suggests that the VESP is of postchiasmal origin. A more detailed topographical study of the scalp and facial distribution of the ERG and its oscillatory potentials has been carried out, with simultaneous recording of the VESP. Two monocular fields of ERG activity have been demonstrated, each having a wide area of distribution and interacting medially. Remnants of the ERG b-wave have been detected at many electrode sites, but they were of different amplitude and morphology from the VESP. Results are also presented from two atypical control subjects and two patients, providing further evidence of the separate genesis of the ERG and VESP.

The optics of fundus examination.

It has been 140 years since the invention of the ophthalmoscope in 1851 by Herman von Helmholtz. Since then, a considerable amount of time and effort has been devoted to improving the clinician's view of the fundus both for diagnostic and therapeutic reasons. Recently, there have been some notable advances in this respect, such as the 90 diopter lens, the "2.2 pan retinal" lens, and numerous "wide angle" fundus-viewing contact lenses to which the Volk Quadraspheric fundus lens has been the most recent addition. This paper is a review of the optical principles underlying the methods of fundus examination currently available.

Pseudophakic accommodation? A study of the stability of capsular bag supported, one piece, rigid tripod, or soft flexible implants.

A group of pseudophakic patients was investigated to determine whether their implants shift along an anteroposterior axis under different conditions of ciliary muscle stimulation. There was no statistically significant change in refraction after either pilocarpine or cyclopentolate administration. A change in anterior chamber depth between the position after pilocarpine and that after cyclopentolate was found. It appears that rigid posterior chamber implants do move backwards on ciliary muscle relaxation, but by a maximum 0.25 mm. This is not thought to represent a mechanical threat to ocular health. It is also not enough to account for the apparent accommodative ability of some pseudophakic patients. The possible causes for this phenomenon are discussed.

The arthroscopic treatment of subacromial impingement.

In order to effectively employ arthroscopic techniques for a subacromial decompression, a thorough understanding of the impingement syndrome and its clinical manifestations is necessary. The authors' preliminary experience with the arthroscopic subacromial decompression suggests excellent results with early return to competitive athletics.

Levels of visual impairment in a day centre for people with a mental handicap.

A prospective study screening for visual impairment in a day centre for people with a mental handicap showed that 30% required spectacles or registration as blind or partially-sighted and a further 20% had previously unknown pathology. Carers were not reliable in identifying visual problems in their charges, and routine screening should be encouraged. High Street optometrists should be able to measure visual acuity in the individuals in this sample excluding those cared for in special care units for whom screening may be less beneficial.

The use of hybrid lenses in management of the irregular cornea.

The use of SoftPerm hybrid lenses was investigated as part of a 10 year retrospective audit of keratoconus in the Contact Lens Service at Nottingham University Hospital which serves a population of approximately one million. During this period, nine patients (14 eyes) were fitted with SoftPerm a lenses for keratoconus. Two further patients (two eyes) were included with a diagnosis of irregular astigmatism and one patient (one eye) was fitted post-corneal graft. Seven patients were regarded as successful hybrid lens wearers and five were regarded as unsuccessful wearers. Of the unsuccessful cases, one patient managed satisfactorily using a rigid gas permeable corneal on the unaffected eye, two patients subsequently had successful corneal grafts, one patient continued with restricted rigid gas permeable lens wear and one patient defaulted.

Therapeutic contact lenses and eyedrops--is there a problem?

Numerous authors have investigated the interactions of contact lenses with their care solutions. Many reported hypersensitivity and toxicity reactions induced by the preservative in the care solution, especially with soft contact lenses. In medical contact lens practice the concurrent use of eyedrops in a patient wearing therapeutic contact lenses is a contentious issue. The usual practice is to prescribe unpreserved drops. In reviewing the literature, we found no evidence of complications using preserved eyedrops with such contact lenses in situ. The reluctance to prescribe preserved topical medication could stem from the evidence relating to contact lens care solutions.

Management options for the flat corneal graft.

The post-penetrating keratoplasty (PK) corneal profile may be unpredictable and visual rehabilitation can be difficult. A case series of 11 such patients with flat corneal topography is presented and their management described. Suture removal may not provide a sufficient re-modelling effect to restore convexity of the cornea to enable satisfactory contact lens fitting and reverse geometry (RG) lenses have an important role.

Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo.

Adoptive T-cell therapy is clinically efficacious in the treatment of select cancers. However, it is often difficult to obtain adequate numbers of tumor-specific T cells for therapy. One method for overcoming this limitation is to generate tumor-specific T cells by retrovirally mediated T-cell-receptor (TCR) gene transfer. However, despite instances of therapeutic success, major obstacles remain, including attaining the survival of retrovirally modified T cells in vivo as well as inducing long-term and multi-gene retroviral expression. Using a murine model of adoptively transferred retrovirally modified CD8(+) T cells, where antitumor immunity was dependent on sustained, multigene expression, we found that in vitro assays are poor indicators of in vivo efficacy. Despite persisting for over 9 months in a nonlymphopenic environment, genetically modified T cells exhibited discordant retrovirally mediated gene expression in vivo not readily evident from initial in vitro assays. In particular, one of the two TCR subunit genes necessary for antigen specificity was selectively lost in vivo. As this discordant gene expression was associated with the loss of antitumor immunity, consideration of these findings may provide guidance in the design, evaluation and application of retroviral vectors for use in the treatment of cancer and other human disease.

Applications of contact lens devices in the management of corneal disease.

Contact lens devices have a variety of therapeutic applications in the management of corneal diseases. A wide range of devices is available, some with very specific indications for use, including scleral lenses, silicone elastomer, collagen shields, large diameter corneal lenses, and silicone hydrogels. The traditional hydrogel contact lens is the most frequently used device and is indicated in at least 80% of cases. Common indications for use are relief of pain, promotion of corneal healing, mechanical protection and support, and control of corneal hydration, often a combination of effects being achieved. Visual improvement may be achieved but this is not the primary role of such devices.

Distance telescopes: a survey of user success.

The distance telescope has a historical reputation for causing difficulties in prescribing and adaptation. Hence, we considered that a retrospective survey of patients at Nottingham Low Vision Clinic might elucidate specific attributes that influence an individual patient's success in using a distance telescope. From 142 patients prescribed distance telescopes since the Clinic's inception, 133 apparently remained users and were mailed a preliminary three-question enquiry about usage of their distance telescopes. The 87 respondents were followed up with questionnaire 2, requesting explicit information about usage, namely frequency, degree of ease or difficulty, and purpose. Older patients required higher magnification (p < 0.025). Seventeen of 74 respondents to questionnaire 2 had various adaptational problems, which are discussed; 57 of 74 patients found their distance telescopes easy to use, and 49 of 57 were frequent users. Thus, ease and frequency are linked (p < 0.05). People tended to use their distance telescopes outdoors and indoors with similar frequency (p > or = 0.29). Adaptation was found to be unrelated to visual acuity, binocularity/monocularity, ocular pathology, or restricted mobility; magnification seemed to be influential, although not significantly. Aging did not significantly impede adaptation. We infer that the universal criterion for selecting treatable patients seems to be personality type. We conclude that adaptation to a device is dependent upon active recognition of its benefits, paralleled with a tolerance of its constraints, which combine to make usage easy and regular on at least one common task.

The interaction between hydrogel lenses and sodium fluorescein. Theoretical and practical considerations.

The interaction between sodium fluorescein dye and hydrophilic contact lenses was assessed quantitatively by spectrophotometry. Absorption of dye into he lens matrix was found to be proportional to the exposure time and also depends on the optical power and water content of the lens. 0.9% saline appeared preferable to oxidising agents as a rinsing solution in decontamination procedures. 3% hydrogen peroxide solution affects the nature of fluorescein such that it becomes colourless and also absorb less incident light, whilst still being retained within the lens. The implications of our findings for practical lens decontamination and theoretical fluorescein/polymer binder are discussed.

Corneal epithelial oxygen uptake rate in diabetes mellitus.

Corneal epithelial oxygen uptake rate (CEOUR) has been measured using a non-invasive polarographic electrode technique in patients with diabetes mellitus (DM), all with varying degrees of retinopathy. CEOUR was found to be significantly reduced in diabetic patients when compared to age-matched non-diabetic controls--Type I diabetics p less than 0.001; Type 2 diabetics p less than 0.01. Known duration of DM and assay of instantaneous, medium and long term glycaemic control showed no significant correlation with CEOUR in the patients studied. These results give further evidence of abnormal corneal metabolism in DM. Reduced CEOUR may be a contributory factor in the pathogenesis of diabetic corneal epitheliopathy.

The sensitive period for anisometropic amblyopia.

Fifty-five children with pure anisometropic amblyopia presented consecutively between 1983 and 1986. Analysis of their records was undertaken with respect to the age at presentation, the initial visual acuity after spectacle correction, and the final acuity attained after treatment. The results show that the final vision achieved does not depend on the age at presentation. The implications of these findings are discussed and their relations to the sensitive period for the development of amblyopia from other causes outlined.

Microtropia versus bifoveal fixation in anisometropic amblyopia.

Microtropia with identity is a unique condition in which amblyopes have parafoveal eccentric fixation in the amblyopic eye in either monocular or binocular viewing, plus a macular scotoma. The condition has previously been described in anisometropic amblyopia. The records of 55 consecutively presenting anisometropic amblyopes were scrutinised and the cases divided into microtropes or non-microtropes (bifoveal fixators). The features of the two groups were then compared to identify factors associated with microtropia and to determine whether microtropes or bifoveal patients responded better to amblyopia therapy. Results show that 45% of anisometropic amblyopes have microtropia rather than bifoveal fixation. There appears to be no association between the microtropic phenomenon and age, depth of amblyopia or amount of anisometropia. Bifoveal patients may respond better to amblyopia therapy although the difference between groups was not great. The sensitive period during which amblyopia may be treated is the same for each group.

Determination of the nodal point position in the pseudophakic eye.

The optics of the schematic eye have been described by Gullstrand and Listing (System of Ophthalmology (ed. H. Kimpton), Vol. 5, C. V. Mosby, London (1970], data being averaged from a series of adult eyes with a crystalline lens. A ray of light from the height of any given object passing, undeviated, through the nodal point will determine the height of its image on the retina. The nodal point positions, therefore, are fundamental in determining image size, and any eye-to-eye variation in a patient will control the amount of aniseikonia. The optics of the pseudophakic eye are described together with a scientific method for determining the nodal point positions, and the implications are discussed.

Aniseikonia: a method of objective assessment in pseudophakia using geometric optics.

There have been various reports in the literature regarding the limits that separate acceptable from disturbing aniseikonia. A criterion value of 5% is often quoted but actual values in pseudophakia may vary from 2% to 10%, depending on the type and position of implant used. In the accompanying paper we have reported a method by which image size can be calculated in the pseudophakic eye. Using this method a series of patients with anterior and posterior chamber implants were analysed and the image size for both eyes of each patient determined. This was compared with the patient's subjective appreciation.