A cyclosporine-based immunosuppressive regimen may be better than tacrolimus for long-term liver allograft survival in recipients transplanted for hepatitis C.

UNLABELLED: Rapid recurrence of severe hepatitis C (HCV) after liver transplantation is a major barrier to survival of the transplanted liver. While cyclosporine (CsA) in vitro has been shown to suppress HCV replication, an effect is not seen with tacrolimus (Tac). Evidence is inconsistent whether or how this translates to clinical practice. To expand the evidence on this issue, we analyzed graft survival and histological outcomes after liver transplantation for HCV hepatitis. METHODS: Using our longitudinal database (1991 onward) graft outcomes for all liver transplant recipients with HCV were evaluated (105 grafts in 97 patients). Severe activity, severe fibrosis, and graft survival were analyzed. All liver biopsies were scored (blinded) according to the Ludwig scale. Immunosuppression was based on prednisone and a calcineurin inhibitor (Tac n = 89, 85%; CsA n = 15, 14%). Comparisons of outcomes using CsA versus Tac therapy were done using survival analysis via the log-rank test. RESULTS: Graft survival was significantly better in the CsA group. Although there was no apparent difference in severe activity (grade 2), there was a statistically significant difference in graft survival without fibrosing cholestatic hepatitis (P = .01) and a trend toward a difference in fibrosis-free survival (P = 0.1). The rate of sustained response to antiviral therapy was twice as high in the CsA group, 50% versus 22% (P = 0.16; NS). CONCLUSIONS: Graft survival in liver transplant recipients with HCV may be greater with CsA-based immunosuppression. There may also be a lower rate of fibrosing cholestatic hepatitis in this group.

Differences in bioavailability between oral cyclosporine formulations in maintenance renal transplant patients.

Previous studies of healthy volunteers and small numbers of transplant recipients have suggested that the oral solution formulation of Sandimmune (cyclosporine [CsA]; Sandoz Pharmaceuticals, East Hanover, NJ) is bioequivalent to the soft gelatin capsule (SGC) formulation. However, there is conflicting evidence as to whether the two formulations are bioequivalent in all patients; to date, there are no published studies that explicitly address their bioequivalence in patients. We conducted a randomized, open-label, two-sequence, two-period, crossover study. Of 20 maintenance renal transplant recipients shown by a screening pharmacokinetic (PK) profile to be poor absorbers of CsA, half were randomized to receive first the SGC formulation and half the oral solution formulation for a period of 7 days. Each patient then underwent a 12-hour PK profile on the last day of the assigned formulation before a crossover to receive the other formulation and repeat the 7-day treatment and PK profile cycle. The results showed that peak and total exposure to CsA was greater with the SGC formulation. The SGC-oral solution ratios indicated an average 38% greater peak and 11% greater total exposure for the SGC formulation (P < 0.01 and P = 0.09, respectively). Trough levels were more similar between formulations, with SGC showing an average of 5% greater troughs (P > 0.10). In our selected population of malabsorbers, the SGC formulation made a difference in drug exposure.

Safety of Neoral conversion in maintenance renal transplant patients: A one-year, double-blind study. NOVARTIS OLN-353 Study Group.

BACKGROUND: Despite the improved pharmacokinetic characteristics of Neoral, some centers have encountered difficulty with the conversion of some patients from Sandimmune to Neoral and have reported precipitation of toxicity and rejection. METHODS: We conducted a randomized, double-blind, parallel-group, multicenter prospective study of stable maintenance renal transplant patients to compare the safety and tolerability of converting from Sandimmune to Neoral (N = 132) versus continuing Sandimmune (N = 130). Patients were studied for one year. The cyclosporine (CsA) dose was adjusted as necessary to maintain site-specific trough whole blood levels. RESULTS: During the study, dose adjustments were frequent in both groups: 67% Neoral versus 65% Sandimmune patients. At study completion, the mean trough CsA levels were comparable; the dose change-from-baseline did not differ statistically between groups. Fewer Neoral (87.1%) than Sandimmune (95.4%) patients reported adverse events, and serious adverse events were comparable. Adverse events related to CsA were not more common in the Neoral group. Renal function measures also implied comparability of the two treatments. Three Neoral versus five Sandimmune patients experienced acute rejection; two Neoral versus five Sandimmune patients experienced chronic graft dysfunction. Two septic deaths occurred in the Neoral group. No grafts were lost. CONCLUSIONS: With careful monitoring, conversion of maintenance renal transplant patients to Neoral can be safely accomplished.

Reduced intrapatient variability of cyclosporine pharmacokinetics in renal transplant recipients switched from oral Sandimmune to Neoral.

Sixty-six renal transplant patients maintained on Sandimmune, the traditional formulation of cyclosporine, participated in an open-label, sequential trial to compare intrapatient variability in drug exposure before and after a switch to Neoral. Three 12-hour cyclosporine pharmacokinetic profiles were obtained over approximately 6 weeks while patients were receiving Sandimmune. Patients were then switched to Neoral, with the dose adjusted as necessary to maintain target trough blood cyclosporine concentrations. At approximately 4 and 6 weeks postconversion, 2 additional pharmacokinetic profiles were obtained. Key pharmacokinetic variables analyzed were area under the concentration-time curve (AUC), maximum concentration (Cmax), and predose trough concentration (C0). Intrapatient variability in drug exposure for dose-normalized mean AUC, Cmax, and C0 was significantly reduced with Neoral, with 50 (76%), 57 (86%), and 45 (68%) patients experiencing reduced variability in AUC, Cmax, and C0, respectively (P < 0.001). Additionally, the total exposure to cyclosporine was more predictable from the trough level of cyclosporine with Neoral; the relationship between AUC and C0 was 0.81 for Neoral at both pharmacokinetic profiling time points but ranged from 0.49 to 0.69 for the 3 Sandimmune time points. The large reductions in intrapatient variability of pharmacokinetic variables for cyclosporine provided by Neoral indicate an improvement in the consistency of drug exposure, which may translate into important clinical benefits.

Clinical assessment of ocular response to a multipurpose contact lens care solution.

The issue of possible adverse effects of contact lens care solutions on ocular health has been raised in the literature. Possible effects of a multipurpose contact lens care solution (Bausch & Lomb ReNu) on eight measures of ocular function were evaluated relative to the effects of physiological saline (Bausch & Lomb Sensitive Eyes). In a randomized, two-treatment, crossover design, all subjects were treated with each of the two solutions on successive weeks. In 73 subjects, comprised of contact lens and non-lens wearers, tear break-up time was measured using the keratometer mire and fluorescein techniques. Measures of autonomic function were vertical palpebral aperture size, amplitude of accommodation, intraocular pressure, pupil size, conjunctival injection, and pupil reactivity. The results indicated that this multipurpose solution provoked no adverse ocular response as determined by the tear break-up time and autonomic functions, and the multipurpose solution was clinically equivalent to physiological saline. These results apply to both contact lens wearers and non-lens wearers. Additional findings speak of the unreliability of the fluorescein method for measuring tear break-up time.

Differences between objective and subjective refractions after radial keratotomy.

BACKGROUND: In patients who are free of pathology, automatic refractions have shown close agreement with the subjective refractions. Clinical experience indicated that the normally strong relationship between objective and subjective refraction is significantly weakened as a result of radial keratotomy. METHODS: Seventy-two patients were refracted before and after surgery, objectively with a Humphrey Model #510 autorefractor and subjectively using a binocular refraction procedure without cycloplegia. All patients were free of ocular disease and had preoperative myopia ranging from -1.00 to -9.00 diopters as determined by the subjective spherical equivalent. RESULTS: The results indicated that the preoperative difference between the mean spherical automatic and subjective refractions was a clinically acceptable 0.25 diopter. However, postoperatively, there was a statistically significant difference of 1.25 D with the automatic refractor determining more myopic refractions. Subsequent analysis revealed that the age of the patient had a direct bearing on this finding with patients less than 40 years of age showing more minus in the automatic refraction than patients 40 years and older. CONCLUSIONS: The postoperative discrepancy between the two refractions may be explained by induced optical aberrations and may contribute towards the visual fluctuations experienced by radial keratotomy patients. It is postulated that the inconsistency in refractive determination is due to optical distortion since the age dependence of this effect may be related to the reduction of pupil size that occurs with aging. In the radial keratotomy patient, the practitioner is faced with a more complex and uncertain refraction that may vary according to refractive procedures used and other factors such as pupil size.

Seroprevalence of Echinococcus granulosus infection in a Uruguayan rural human population.

Serological tests using hydatid cyst fluid (HCF) are useful as a primary screen for detecting asymptomatic infections due to Echinococcus granulosus in human populations. An enzyme-linked immunosorbent assay (ELISA) performed with whole sheep HCF was used to determine the prevalence of hydatid antibodies in a rural human population in Uruguay. In order to eliminate cross-reactions with sheep proteins in HCF, 1% normal sheep serum was added to each human serum before testing. ELISA seropositives were further tested using the double diffusion test (DD5) and confirmed where possible by ultrasound and X-ray examination. Serum samples were obtained from 420 individuals inhabiting rural areas in the Department of Paysandu (160), Rivera (21) and San José (239). An overall seroprevalence of 1.24% was obtained. Two of 17 seroreactors were subsequently proven to have hydatidosis. These results confirm and extend previous studies indicating an unusually high prevalence of E. granulosus infection in the Uruguayan population.

The relationship between eye position and egocentric visual direction.

Hering's model of egocentric visual direction assumes implicitly that the effect of eye position on direction is both linear and equal for the two eyes; these two assumptions were evaluated in the present experiment. Five subjects pointed (open-loop) to the apparent direction of a target seen under conditions in which the position of one eye was systematically varied while the position of the other eye was held constant. The data were analyzed through examination of the relationship between the variations in perceived egocentric direction and variations in expected egocentric direction based on the positions of the varying eye. The data revealed that the relationship between eye position and egocentric direction is indeed linear. Further, the data showed that, for some subjects, variations in the positions of the two eyes do not have equal effects on egocentric direction. Both the between-eye differences and the linear relationship may be understood in terms of individual differences in the location of the cyclopean eye, an unequal weighting of the positions of the eyes in the processing of egocentric direction, or some combination of these two factors.

Should level of measurement considerations affect the choice of statistic?

The belief that the level of measurement (nominal, ordinal, interval, ratio) achieved in the data constrains the type of statistic that may be used legitimately for analysis is examined in general, and in an optometric-vision science context. Theoretical considerations indicate that statistical statements about the data may be made independently of the level of measurement, and that although researchers must be concerned about the quality of their measurement, the role of measurement theory is in the interpretation of the meaning of the investigation's results as a whole not in the governance of the choice of statistic. Empirical studies indicate that measurement considerations can be ignored for the purposes of testing the null hypothesis with little or no resultant error. Finally, adherence to the belief that level of measurement considerations limits statistical choice would result in the use of generally less powerful statistical tests--an undesirable and, all things considered, an unwarranted consequence.

Problem of between-eye correlation for statistical hypothesis testing: rabbit corneal thickness.

The two eyes of a subject often yield correlated data. Statistical analysis which treats correlated data as if it were independent is most likely to be biased toward statistical significance; that is, the probability of a type I error is likely to be inflated. To illustrate the importance of lack of independence to the inferential process, data from an experimental design commonly used in optometric research are used to demonstrate (1) the potential magnitude of between-eye correlation, (2) the statistical bias toward a significant outcome when the between-eye correlation is ignored via inappropriate analysis, and (3) simple ways by which the bias can be avoided. The researcher must be aware of the between-eye correlation which exists for the particular effect under study, and the statistical bias that ensues from the correlation when the data are not handled correctly.

Axial chromatic aberration of the human eye: frequency or wavelength?

The axial chromatic aberration of the human eye is nearly perfectly described by a linear function when expressed in terms of frequency rather than wavelength. Since linear functions are simple to work with and more readily understood, there are advantages for the expression of these data in terms of frequency.

Visual localization of briefly presented peripheral targets.

Reported here are the results from two experiments designed to investigate Mateeff and Gourevich's (1983, 1984) claim that adult observers make large constant errors when judging the direction of briefly presented peripheral targets, with respect to a continuously visible scale. Experiment 1 involved a virtually exact duplication of Mateeff and Gourevich's paradigm. Experiment 2 involved adjusting the position of a light emitting diode (LED) so as to match the direction of a LED previously flashed in the periphery. No significant constant errors were found in either experiment.

Does impaired contrast sensitivity explain the spatial uncertainty of amblyopes?

We investigated the possibility that the spatial imprecision of amblyopic eyes can be accounted for by the relative insensitivity to contrast that has been documented for these eyes. Thresholds for the discrimination of spatial misalignment, a measure of spatial uncertainty, were determined for three amblyopes and one normal for targets ranging in contrast from detection threshold to 99%. We found that spatial uncertainty was greater in amblyopic eyes than non-amblyopic eyes for targets equally above contrast threshold, and when the targets were presented at threshold contrast to the nonamblyopic eyes and at 99% contrast to the amblyopic eyes. Our results fail to support the possibility that the spatial imprecision of amblyopic eyes can, in general, be attributed to reduced contrast sensitivity. Different neural abnormalities are presumed to limit amblyopes' performance on different spatial tasks.

Effects of luminance on the visual acuity of strabismic and anisometropic amblyopes and optically blurred normals.

Evidence is accumulating to suggest fundamental differences between strabismic and anisometropic amblyopia. We explored differences in these amblyopes by assessing the effects of luminance on optotype acuity, using targets that ranged from photopic to low mesopic levels. Our results show that reducing luminance has less of a detrimental effect on the acuity of strabismic than anisometropic amblyopic eyes. Furthermore, the effect of decreasing luminance on the acuity of optically blurred normal eyes mimicked the effect we found for anisometropic amblyopic eyes. These results are consistent with the hypothesis that the fundamental deficit in anisometropic amblyopia is impaired resolution while in strabismic amblyopia the fundamental deficit is impaired spatial directionalization.

Two factors affecting saccadic amplitude during vergence: the location of the cyclopean eye and a left-right bias.

Saccades occurring during vergence have been reported to differ in amplitude depending on whether the saccade drives the eyes leftward or rightward. Furthermore, this difference varies in degree and direction among individuals. We examined two explanations of the variation--that it is the result of the cyclopean eye being nearer to one eye, and that it is the result of a pervasive bias, within an individual, to make larger saccades either leftward or rightward. Examination of the saccades of 14 subjects, recorded during both divergent and convergent movements that required leftward or rightward saccades, shows that neither explanation alone provides an adequate account of the differences observed. However, statistical analysis (ANOVA) indicates that almost 60% of the total variation in the observed saccadic amplitudes is related to the two explanations taken together. We speculate that both influences act on the saccade in a given individual, and that the amplitude manifested depends on the relative magnitudes of the two influences within that individual.

The effect of optical blur on visual acuity for targets of different luminances.

We studied the effect of 1.25 D of optical blur on visual acuity at luminances ranging from photopic to low mesopic levels. Optical blur reduces acuity at all luminances tested, this reduction being fourfold at a high photopic level (170 cd m-2) and twofold in low mesopia (0.017 cd m-2). The reduction of visual acuity with blur at low luminances is greater than might be expected from a spatial frequency analysis of vision.

Spatial aberrations and acuity in strabismus and amblyopia.

Spatial uncertainty and distortion were quantified from judgement of the horizontal position of a flashed 0.5 deg vertical line with respect to a flanking reference target in strabismics with and without reduced acuity. Spatial uncertainty was outside the range of 30 normal eyes in all of 23 strabismic amblyopic eyes (visual acuity = 20/40 or worse) and in 20 of 22 squinting eyes with 20/30 or better acuity. Abnormal spatial distortion was found in 16 amblyopic and 10 squinting eyes. In the deviated eyes of the strabismics, the extent of spatial uncertainty and distortion correlated with visual acuity. Spatial aberrations were not accounted for by strabismics' unsteady or eccentric fixation, nor were they mimicked in normal eyes when visual acuity was artifically reduced. The authors suggest that spatial uncertainty and distortion represent the primary abnormalities in strabismics and produce deficits of visual acuity according to their severity.

Stereo-deficients and stereoblinds cannot make utrocular discriminations.

In two separate experiments, we show that stereo-deficient observers are no better than stereonormals at discriminating the eye-of-origin of a monocular stimulation. Stereo-deficient observers are considered to have a preponderance of monocular neurons throughout their visual system, including the visual cortex. The results indicate that, in spite of their clear anatomical and physiological structure, such monocular neurons do not convey eye-of-origin information to consciousness.

Utrocular discrimination is not sufficient for utrocular identification.

The distinction between reliability and validity is critical in examining utrocular identification. Four experiments demonstrated that two cues that lead to reliable discrimination do not lead to valid identification. Experiment 1 showed that, in the condition in which a stimulation of the right eye produced a visual direction toward the right and a stimulation of the left eye toward the left, there was a preponderance of correct responses. In the condition in which a stimulation of the right eye produced a visual direction toward the left and the left eye toward the right, there was a preponderance of incorrect responses. Experiment 2 showed that covariation of responses with visual direction decreased when feedback was provided because subjects sought other cues. Experiment 3, which included binocularly deficient subjects, showed that a feeling-in-the-eye is associated with the eye stimulated by a greater change in luminance rather than the eye stimulated by the target stimulus. When the luminance change was greater in the target eye, the feeling led to reliably correct responses, but when the luminance change was greater in the nontarget eye, it led to reliably incorrect responses. Experiment 4 indicated that the proportion of correct responses covaries with the degree of change in the luminance of the nontarget eye. The responses varied from reliably incorrect identifications, through unreliable identifications, to reliably correct identifications. These findings are consistent with the idea that stimulation of either eye is "projected" to the cyclopean eye.