Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Cones survive rods in the light-damaged eye of the albino rat.

Exposure to constant light causes extensive rod photoreceptor damage but spares the photopic system in albino rats. The rod branch of the dark-adaptation curve shows considerable elevation in threshold; the cone branch is hardly affected. Longer exposure and chromatic adaptation suggest that there are three cone mechanisms with peaks near wavelengths of 450,520, and 560 nanometers.

Cone inputs to ganglion cells in hereditary retinal degeneration.

The photoreceptor layer degenerated, but cone nuclei apparently devoid of outer segments were retained in retinas of aged rats of the Royal College of Surgeons strain from which optic tract activity was recorded. Measures of sensitivity showed these single axons of retinal ganglion cells to have photopic spectral responses. Cone remnants containing a cone pigment may be the photoreceptive elements in these retinas.

Evaluation of serum CA 125 levels in patients with pelvic pain related to endometriosis.

The aim of the study was to investigate the clinical value of the serum CA 125 level for diagnosing and determining the severity of endometriosis and pelvic pain associated with endometriosis. Eighty-six women who underwent operative laparoscopy were enrolled. Sixty-nine women with endometriosis and 17 without endometriosis participated in this study. In all of the patients, endometriosis was diagnosed and classified into stages according to the Revised American Fertility Society (R-AFS) classification. The mean serum CA 125 levels were determined in each patient. We also investigated the relationship between serum CA 125 concentration and the intensity of dysmenorrhea and dyspareunia in the study group. The mean serum CA 125 levels of women with endometriosis were higher than those of the control group (p<0.050). However, the mean serum CA 125 levels were higher in stage IV than in other stages of endometriosis according to the R-AFS classification. On the other hand, the percentage of patients with serum CA 125 levels >35 U/mL was elevated in the subgroups with severe dyspareunia and severe dysmenorrhea versus the asymptomatic subgroup but the differences had no statistical significance. In conclusion, CA 125 serum levels were related to endometriosis and R-AFS score in the evaluated patient series. No correlation was found between serum levels of CA 125 and pelvic pain in patients with endometriosis.

Expansion of the half retinal projection to the tectum in goldfish: an electrophysiological and anatomical study.

The topographical retino-tectal projection of goldfish was electrophysiologically mapped at various intervals after surgical removal of the nasal half of the retina and pigment epithelium. The remaining projection was initially restricted to the appropriate rostral half of the tectum, even if the nerve was crushed and allowed to regenerate. But later, after 137 days or more, it showed a progressive expansion onto the foreign caudal half of the tectum. The magnification factor, the number of micrometers of tectum per degree in the visual field, doubled in the rostro-caudal but not in the medio-lateral direction. Analysis of the sequence of the expansion showed that a few fibers originally projecting nearest the denervated area were the first to spread over it. Then, progressively more fibers moved caudally until a nearly uniform representation of the half retina was established on the tectum. Radioautography also demonstrated that retinal fiber terminals had invaded the caudal tectum. The retinae of these fish were also examined histologically. The density of ganglion cells had not increased, but they consistently showed the axonal reaction. This was not found to be associated with any initial surgical trauma, but rather with the movement of their fiber terminals within the tectum. Frozen sections through half retinal and normal eyes, were cut and photographed for comparison of ocular geometry. Operated eyes were normal except for a slight but consistent loss of ocular volume. Analysis of the optical geometry showed that recording with fish in air produced two effects: Myopia (10 degrees blur circle, or less) and enlargement of the visual field by 15 percent to 20 percent.

Cells in the pretectal olivary nucleus are in the pathway for the direct light reflex of the pupil in the rat.

Extracellular microelectrode recordings from 148 single cells in the pretectum of the hooded rat were classified according to their temporal response properties to light stimulation of their retinal receptive fields. Fifty-six cells were classified as tonic-on cells, 22 cells were classified as tonic-off cells, and 53 cells were classified as phasic cells. Seventeen cells could not be assigned to one of these 3 groups. The diameters of the receptive field centers of the tonic-on pretectal cell were clustered about a mean of 31 degrees and the temporal response of these cells was sustained. Constriction of the contralateral pupil was produced by electrical stimulation through the recording electrode at sites containing tonic-on pretectal cells, but not at sites containing tonic-off pretectal cells or phasic pretectal cells. For this reason, we argue that tonic-on cells are likely to mediate constriction in the light reflex of the rat's pupil. Receptive field maps together with electrolytic marking lesions at recording and stimulation sites showed that tonic-on pretectal cells are retinotopically organized and are aggregated in a strip running from the dorso-medial tip of the pretectum to the ventro-lateral boundary. The anatomical distribution of these cells is coextensive with the region known as the pretectal olivary nucleus (PO) in the rat. Using fine microelectrodes, recordings were obtained from 27 axons presumed to be of optic origin (fibers). Of these, 14 were tonic-on, 10 were phasic, 2 were tonic-off, and 2 were unclassified. Recordings from tonic-on fibers were obtained near tonic-on pretectal cells, typically in the most dorsal light-responsive region of the pretectum. These fibers were activated by single pulse electrical stimulation of the optic chiasm. The mean receptive field center diameter of 6 tonic-on fibers was 10.1 degrees, or about a factor of 3 less than that of pretectal tonic-on cells. The mean conduction velocity of 14 tonic-on fibers was 3.1 m/s. We argue that the tonic-on cells of the PO serve to integrate signals from tonic-on center retinal ganglion cells with adjacent receptive fields to provide signals for constriction of the pupil to neurons in the oculomotor nucleus.

The ratio of L cones to M cones in the human parafoveal retina.

We present psychophysically-based estimates of the relative numbers of long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cones in the parafovea of three color-normal trichromats. Using methods previously applied to the fovea centralis, we obtained estimates of the relative numbers of L and M cones at retinal eccentricities of 1.0, 1.5, 2.0, 3.0, and 4.0 deg along the horizontal meridian of the temporal retina. Results for three observers indicate that the L to M cone ratio remains approximately invariant from the fovea to 4.0 deg eccentricity, with a mean ratio near 2:1.

Changes in visual sensitivity with age in rats with heredity retinal degeneration.

Hereditary retinal degeneration in the Royal College of Surgeons (RCS) strain of rat has been shown to produce extensive loss of photoreceptors and a corresponding decline of the electroretinogram, ganglion cell sensitivity, and the sensitivity of the pupillary light reflex. The behaviorally measured thresholds of RCS rats, on the other hand, are reported to be comparable to those for age-matched controls. We report here, that our own behavioral measurements show a clear difference between RCS rats and age-matched controls between four to twelve months of age. The difference in thresholds between RCS and control rats is about three long units at four months of age, and this difference progressively increases until at twelve months, we measure threshold differences of over seven log units.

Retinal sensitivity measured by the pupillary light reflex in RCS and albino rats.

The effects of retinal degeneration on the sensitivity of the retina were studied in the Royal College of Surgeons (RCS) rat by measuring the light reflex of the pupil in response to ganzfeld (full field) flashes. Light reflex thresholds were measured for animals from 32 to 683 days of age, and an age-related decrease in sensitivity of 5.2 log units (maximum) was measured. In contrast, thresholds for non-dystrophic albino controls increased only slightly during a comparable period. RCS rat thresholds increased more for short wavelength light than for long wavelength light. The end result was an altered action spectrum of the light reflex which largely, but not exclusively, reflected cone function. Even in cases of advanced degeneration the light reflex thresholds we measured showed significant input from rods. Pupiliary dark adaptation measured following ganzfeld bleaches (10%) with test stimuli of two different wavelengths revealed two mechanisms; a photopic mechanism (gamma max = 520) determined thresholds early in dark adaptation, but later a scotopic mechanism (gamma max = 500) participated in the light reflex.

The size of the pool for bleaching adaptation in human rod vision.

We present new psychophysical estimates of the size of the rod pool for bleaching adaptation in the human retina. We estimate that at 5 deg nasal eccentricity in the human retina the size of the adaptation pool for rods is between 5 and 7.5 min arc. This estimate is compatible with the extent of the dendritic spread of rod bipolars located in this region of the primate retina and with the area occupied by roughly 50 rods in this parafoveal region of the human retina. Thus a candidate for the site of adaptation is the bipolar cell whose receptive field is comprised of approx. 50 rods. These estimates represents the lowest measurements to date of the size of the adaptation pool for rods.

The density of cones in the fovea centralis of the human dichromat.

We present estimates, based on psychophysical measurements, of the density of cones in the fovea centralis of human dichromats. The estimates for a group of three protanopes and three deuteranopes (this study) were compared to the estimates of the density of cones in a group of six color normal trichromats from previous studies (Cicerone & Nerger, 1985, 1989). The results support the conclusion that the density of cones in the fovea centralis of the dichromat is comparable to that of the color normal trichomat. These results tend not to support a model of dichromacy in which a class of cones as well as the associated pigment are lost in the dichromatic eye. Instead, dichromacy appears to involve a loss of one of the three visual pigments associated with human trichromacy, with a retention of the full numbers of cones.

The relative numbers of long-wavelength-sensitive to middle-wavelength-sensitive cones in the human fovea centralis.

The determination of the relative numbers of different cone types in the human retina is fundamental to our understanding of visual sensitivity and color vision; yet direct measurement which provide this basic information have not previously been made for all cone types. Here we present a model which links the detection of a test light of small dimension to the number of cones contributing to detection of the light. We selectively isolated either the long-wavelength-sensitive (L) or the middle-wavelength-sensitive (M) cones, by choosing combinations of wavelengths of adapting backgrounds and tests to favor detection by the cone class of interest. Our model was applied to the detection functions measured for six color normal observers to obtain estimates of the relative numbers of L to M cones. Our estimates ranged between 1.46 and 2.36 for our observers with a mean value near two L cones for every M cone in human fovea centralis.

The spatial arrangement of the L and M cones in the central fovea of the living human eye.

Experiments designed to estimate the placement of L and M cones in fovea centralis of the living human eye are presented. Hyperacuity performances for two observers were measured for the full and the separate L and M cone submosaics using 2-dot chromatic stimuli on cone-selective adapting backgrounds. Simulated performances, based on an ideal observer model, were generated for all possible mosaics by varying L and M cone relative numerosity and spatial configuration. The best match between the simulated and measured performances determined the solution mosaic. Each observer's solution mosaic contained more L than M cones, randomly arrayed as assessed by statistical tests.

Color-specific depth mechanisms revealed by a color-contingent depth aftereffect.

Models of stereoscopic depth perception for both natural and random-dot images have focused mainly on the matching of achromatic features of binocular images. Recently, a growing body of research has investigated whether chromatic features can also contribute to the construction of stereoscopic depth. Here we present experiments yielding color-contingent depth aftereffects comparable in magnitude to those measured after adaptation to achromatic stimuli as evidence of neural mechanisms tuned to both color and depth. Furthermore, we report that the locus of the combined processing of color and depth is likely to lie beyond the site of binocular matching.

The spatial arrangement of L and M cones in the peripheral human retina.

The spatial arrangement of L and M cones in the human peripheral retina was estimated from red-green color naming of small test flashes (0.86 min of arc, 555 nm, constant intensity) presented at different locations (grid with 1.5 min of arc steps) centered at 17 degrees temporal eccentricity. Simulated red-green color naming ratings were generated by a model based on an ideal observer for all possible patterns of placement and relative numerosities of L and M cones, constrained by the anatomical data on the statistics of cone spacing at this retinal location. The best matching simulated performance as compared to the human observer's data determined the cone array most likely to produce that observer's color naming results. The mosaics for two color normal observers showed L and M cones randomly arrayed over this retinal region. Consequences of random cone placements for spectral sampling and color opponency are discussed.

Equilibrium hue judgements of dichromats.

It is generally held that protanopes and deuteranopes see only regions of blues and yellows in the visible spectrum, with an achromatic point, called the neutral point, separating these regions. Considerations of a zone model of color vision for the dichromatic observer led us to predict that a reduced form of red/green discrimination would allow equilibrium blue judgements to be made by protanopes. We show that protanopes can make equilibrium blue determinations with as much reliability as they make neutral point settings. Our results indicate that protanopes but not deuteranopes are able to rely on a reduced form of red/green discrimination in the short wavelength part of the spectrum. Protanopes describe wavelengths longer than the neutral point as yellow. Between the neutral point and equilibrium blue, different wavelengths are described as having varying aspects of blue and green; and short of equilibrium blue they appear reddish blue. For dueteranopes, the spectrum longer than the neutral point appears yellow, and short of it, blue. The results of our experiments showing that the protanopic equilibrium blue is invariant with intensity variations, as it is in the trichromat, add support to the idea of a reduced form of red/green discrimination for protanopes. Our results also allow the evaluation of various models of protanopia.

The spread of adaptation in human foveal and parafoveal cone vision.

We investigated the spread of bleaching adaptation for human cone vision in the central fovea and at an eccentricity of 5 deg in the nasal retina. Cone thresholds measured after adaptation to a grating bleach were compared to those measured after a uniform bleach. We conclude that the foveal and parafoveal cone systems show excellent localization of the effects of adaptation. For areas 2.5-5 min removed from the bleach, our measurement show only small sensitivity losses amounting to between 0.10 and 0.25 log unit elevation in threshold, after taking account of optical scatter.

Consensual pupillary light reflex in the pigmented rat.

We measured the pupillary light reflex (PLR) in 5 pigmented, Long Evans rats (under urethan sedation) in three conditions: direct stimulation, consensual stimulation, and a control condition designed to measure the effects of stray light. The average constriction (maximal amplitude) produced by a ganzfeld stimulus delivering 1.6 log quanta absorbed per rod per sec for a duration of 3 sec was measured to be 0.78 +/- 0.07 mm for the direct PLR, 0.67 +/- 0.06 mm for the consensual PLR, and 0.07 +/- 0.029 mm for the control condition. We corrected the consensual measurement for each rat by subtracting the value of the control (stray-light induced) constriction. A comparison of the corrected consensual constriction to the direct constriction showed that, on average, the consensual constriction attained an amplitude of 78% of the direct constriction. Our findings contradict claims that the consensual pupillary light reflex is absent in rodents. Although our results are in agreement with findings showing bilateral projections of the retina to the pretectum (which subserves the pupillary light reflex) in the rat, the consensual-to-direct ratio we report is higher than might be expected from anatomical estimates of the overall proportion of uncrossed to crossed optic fibers in the rat.