Cup to disc ratio by optical coherence tomography is abnormal in multiple sclerosis.

OBJECTIVE: To identify and characterize cup to disc ratio (CDR) and related optic nerve head abnormalities in multiple sclerosis (MS) using spectral domain optical coherence tomography (OCT). BACKGROUND: While CDR is routinely assessed by ophthalmologists in the evaluation of glaucoma, CDR and related optic nerve head metrics remain largely unexplored in MS. DESIGN/METHODS: Cirrus-HD (high density) OCT was used to evaluate average CDR, vertical CDR, optic disc area, optic cup volume, and neuro-retinal rim area in 105 MS patients and 88 age-matched healthy individuals. High-contrast (100%) visual acuity, 2.5% low-contrast letter acuity and 1.25% low-contrast letter acuity were assessed in 77 MS patients. Two-sample t-tests were used in the analysis of OCT-derived optic nerve head measures between healthy controls and MS patients. Multivariate regression (accounting for age and gender) was used to assess relationships between optic nerve head measures and visual function. RESULTS: Average CDR (p=0.007) and vertical CDR (p=0.005) were greater in MS patients compared to healthy controls, while neuro-retinal rim area was decreased in MS patients (p=0.001). CDR increased with retinal nerve fiber layer (RNFL) thinning (r=-0.29, p=0.001). 2.5% low-contrast (p=0.005) and 1.25% low-contrast letter acuity (p=0.03) were lower in MS patients with higher vertical CDR. CONCLUSIONS/RELEVANCE: CDR (as determined by spectral domain OCT) is abnormal in MS and correlates with visual function. OCT-derived CDR and related optic nerve head metrics may represent an objective measure by which to monitor disease progression, and potentially neuroprotection, in therapeutic MS trials.

Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies.

OBJECTIVE: To evaluate the retinal nerve fiber layer (RNFL) thickness and macular volume in neuromyelitis optica (NMO) spectrum patients using optical coherence tomography (OCT). BACKGROUND: OCT can quantify damage to retinal ganglion cell axons and can identify abnormalities in multiple sclerosis and optic neuritis (ON) eyes. OCT may also be useful in the evaluation of patients with NMO. METHODS: OCT and visual function testing were performed in 26 NMO spectrum patients with a history of ON, 17 patients with isolated longitudinally extensive transverse myelitis (LETM) without ON, 378 patients with relapsing-remitting multiple sclerosis (RRMS), and 77 healthy controls at 2 centers. RESULTS: Substantial RNFL thinning was seen in NMO ON eyes (63.6 microm) relative to both RRMS ON eyes (88.3 microm, p < 0.0001) and control eyes (102.4 microm, p < 0.0001). A first episode of ON was estimated to cause 24 microm more loss of RNFL thickness in NMO than RRMS. Similar results were seen for macular volume. ON also was associated with more severe visual impairment in NMO spectrum patients than in RRMS patients. Eyes in the LETM group and unaffected NMO eyes were not significantly different from controls, though conclusions about these subgroups were limited by small sample sizes. CONCLUSIONS: Optical coherence tomography (OCT) shows more severe retinal damage after optic neuritis (ON) episodes in neuromyelitis optica (NMO) than in relapsing-remitting multiple sclerosis. Identification of substantial retinal nerve fiber layer loss (>15 microm) after ON in a non-multiple sclerosis patient should prompt consideration of an NMO spectrum condition. OCT may be a useful tool for the evaluation of patients with NMO.

Retinal architecture predicts pupillary reflex metrics in MS.

OBJECTIVE: To study the relation of retinal nerve fiber layer thinning to clinical and physiologic measures of visual function in patients with MS or neuromyelitis optica and unilateral optic neuropathy. METHODS: We studied a cohort of control subjects (n = 64) and patients (n = 24) with evidence of unilateral thinning of their average retinal nerve fiber layer as measured by optical coherence tomography in order to characterize the relationship between ganglion cell axonal degeneration and its impact upon vision and pupillary light reflex metrics using infrared pupillometry. RESULTS: When compared to the normal fellow eye, and with respect to normal subjects' eyes, we confirmed significant abnormalities in retinal nerve fiber layer thickness, total macular volume, low-contrast letter acuity, and pupillary reflex metrics in the eye with the thinner retinal nerve fiber layer. For each -5% change in pupil diameter, there was a corresponding 7.1 Amicrom reduction in the average retinal nerve fiber layer thickness. There was a significant difference between the pupillary metric of percent change in diameter and a decrease in low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a substantial 3.4 line loss of low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a 0.2 mm(2) decrease in total macular volume (P < 0.001). CONCLUSION: These findings further corroborate the hypothesis that the retina can be utilized as a model to advance our understanding of the mechanisms of axonal and neurodegeneration, and the corresponding impact of these processes upon the pathophysiology of MS and related disorders.

Social anxiety and social performance: why don't we see more catastrophes?

This article surveys the recent literature with regard to social phobia and social anxiety as they affect social performance. It suggests that some of the inconsistent findings in this area might be alleviated by the application of Fazey and Hardy's (1988) catastrophe model to ongoing research in the area of social performance.

Mood and forbidden foods' influence on perceptions of binge eating.

This study consists of two experiments investigating the effects of induced mood and food type on perceptions of eating in imagined and real eating situations. A total of 212 female undergraduates representing the continuum of bulimic symptomatology were induced with either elated or depressed moods using a standardized mood-induction procedure. They were then either asked to imagine themselves in a situation with either forbidden or non-forbidden foods (Experiment 1) or else were presented with a buffet of forbidden or non-forbidden foods and asked to eat (Experiment 2). Participants subsequently reported their perception of their eating behavior (i.e., amount of control, meal rating: from a snack to a binge; and meal feeling: from great to bad). Results revealed limited support for affect regulation models of bulimia nervosa when the participants consumed food, but no support for the theory when they imagined eating. Conversely, forbidden foods were found to influence perceptions in the imagined eating situation, but not when the participants ate. Implications of these results are discussed.

Social anxiety and its effects on performance and perception.

This study examined whether the socially anxious show deficits in performance on a social task as well as how their anxiety and competence relate to judgments they make about themselves and others. Ratings from a panel of judges were used to compare men of high and low social anxiety on their performances in a simulated job interview. Participants also viewed videotapes of themselves and others and rated responses for content, fluency, nonverbal, and global competence. Contradicting predictions of a performance deficit model, high levels of social anxiety had no detrimental effect on participants' performance or on their ability to judge their own performance. In contrast, observer-rated competence was related to a number of significant effects for social judgment tasks. Implications for treatment of social anxiety and research on social anxiety are discussed.

Development of the Multi-Trait Personality Inventory (MTPI): comparison among four Chinese populations.

Anemic approach was adopted to develop a culture-specific instrument for the assessment of Chinese personality. The Multi-Trial Personality Inventory (MTPI) was administered to 1,673 men and 944 women in four major Chinese populations. It was found that Chinese in mainland China, Taiwan, Hong Kong, and the United States possess some common traits deeply rooted in the Chinese culture characterized by Confucian thoughts (e.g., self-discipline and moderation) and some additional traits nurtured by their respective environments. Consequently, findings of this study lent support to the hypothesis that, in spite of superficial discontinuities, there are basic continuities in the personality traits of mainland and overseas Chinese. The cross-cultural differences in personality were examined from a political-social perspective and also explained with a cultural-ecological model. In the development of the MTPI, a new methodology that relies on forming factor-consistent clusters was employed to deal successfully with the problem of complex factor space.

A direct nomination method for the identification of neglected members in children's peer groups.

This paper describes two studies that compared a direct nomination method for identifying the neglected members of children's peer groups with the commonly used derived social impact score method. In the first study, first-grade children were asked to nominate peers to a neglect dimension in addition to the traditional sociometric dimensions of like and dislike. Both neglect and social impact scores were quite stable over time. Social impact scores were significantly more stable than neglect scores when the full range of scores was considered; however, when the two measures were compared in terms of the stability with which children are identified as extreme scores, the two methods were equally reliable. In spite of this similarity, the two measures identified different children as extreme scorers on each occasion. In an attempt to explain this confusion, the second study investigated the patterns of correlations between observed behaviors and directly nominated neglect, like, and dislike scores and derived social preference and social impact scorers. Results indicated that directly nominated neglect scores were correlated with observed behavioral variables that are consistent with the notion of social neglect. Derived social impact scores were related to observed behavioral variables exactly as their component parts (directly nominated like and dislike scores) were related to these variables; thus, they carried little new information.

WR-2721 entry into the brain across a modified blood-brain barrier.

Radioprotection of the CNS by WR-2721 has not been possible because of its inability to cross the blood-brain barrier (BBB) and so gain access to the neural tissue. Modification of the BBB using hypertonic arabinose (1.8 m), injected via the internal carotid artery (ica), permitted entry of ip-injected [14C]WR-2721 into the ipsilateral cerebral hemisphere. The BBB-modified hemisphere had a 5.34-fold increased uptake compared to nonmodified controls. Delivery as a bolus via the ica further enhanced uptake after BBB opening; WR-2721 was 3.73 times greater than by ip injection. A 20-fold increase of WR-2721 brain uptake has been calculated for ica administration with the BBB opened as compared to the ip route without BBB modification. Toxicity of ip-administered WR-2721 with the BBB open was only 1.4 times greater than non-modified controls and 1.96 times more toxic when delivered via the ica. These data demonstrate significant uptake of WR-2721 into the CNS, a previously unprotected organ, and provide a model for future radioprotective studies.

The carboxylmethylation of cerebral membrane-bound proteins increases with age.

Recently, we have characterized a membrane-bound (mb) component of brain protein carboxylmethyltransferase II (PCMT) which effectively carboxylmethylates endogenous mb methyl-accepting proteins (MAPs). (Neurochem. Int., 10 (1987) 155). We have also shown that exposing mb-MAPs to mild alkali leads to a marked increase in their recognition by PCMT. Since one of the likely consequences of the alkaline treatment appears to be the deamidation of selected protein-bound asparagines or aspartates, followed by the formation, in their place, of D-or L-isoaspartates, it is reasonable to assume that mb-MAPs constitute unique targets for the mb-PCMT because they contain such unnatural aspartate residues. Testing the relevance of this notion to the aging of cerebral mb-MAPs we focus in this report on age-related changes involving mb-MAPs. When two-or six-times washed (in 50 mM NaPO4 buffer, pH 6.5) 17,500 g, 30-min membranes or Percoll-gradient purified synaptic membranes were prepared from young (3-4 months) and old (11-12 months) rat brains and were incubated with 20 microM [3H]methyl S-adenosyl-L-methionine at pH 6.0, mb-MAP carboxyl[3H]methylation was significantly more intense in the old than in the young membranes, no additional increase being noted at 28-35 months. Mb-MAP carboxylmethylation increases were confirmed over a wide range of membrane protein concentrations and incubation times and are taken to reflect age-related modifications of the primary structure of susceptible mb-MAPs. To investigate these, we incubated young and old membranes, as well as their Lubrol-Px (1%) extracts (30 min, 0 degree C), with 0.05 M NH4OH for 90 min at 37 degrees C, a treatment which left PCMT activity largely unaffected. Our findings reveal that the effect of the NH4OH treatment on the generation of carboxylmethylatable sites was markedly smaller in "old" than in "young" proteins, suggesting that "new" carboxylmethylatable sites are generated in susceptible mb-MAPs in situ, by a process accompanying, or otherwise marking, the natural aging of neural membrane proteins.

Transplacental uptake of WR 2721 by the rat embryo.

On day 14 post-conception, near the end of the period of major organogenesis, pregnant rats were injected intravenously or intraperitoneally with WR 2721 spiked with 14C-WR 2721. The radioprotectant was shown to cross the placenta rapidly when administered by either route, and the concentration of WR 2721 in the embryos, placentae, and maternal blood plasma was determined during the period 5 to 90 minutes following administration. The concentration of WR 2721 increased continuously in the embryos during this period and did so against a decreasing concentration in the maternal blood. Injection of WR 2721 at 100 mg/kg of maternal body weight resulted in the presence of 8-9-mg/kg embryo weight; this embryo level is about 1/2 the injected dose of WR 2721 currently being used in human radiotherapy trials, that is, 20 mg/kg (740 mg/m2) body weight. Previous toxicity studies of 9, 11, and 14 day rat embryos have shown that this 100 mg/kg dose is much below the level which produces embryotoxic effects.

Effect of WR-2721 on fetal development in the rat.

The radioprotector WR-2721 has been shown to radioprotect all tissues studied except the central nervous system. However, it has not yet been used to radioprotect the fetus. In this study we determined that [14C]WR-2721 injected into pregnant rats quickly passed the placenta and was concentrated by the fetus. In addition, we evaluated the toxicity of WR-2721 (2.5-600 mg/kg) to pregnant rats and their fetuses during the period of major organogenesis at Days 9, 11, and 14 postconception. Pregnant animals were only slightly more (10%) sensitive (LD50, 580 mg/kg) to WR-2721 than nonpregnant cohort animals (LD50, 640 mg/kg). At concentrations of 50 mg/kg or less there was a small but statistically significant increase in fetal deaths, while at doses greater than 300 mg/kg a larger degree of fetal mortality occurred. Maximal fetal weight loss, to about 84% of control, was found at 500 mg/kg. No changes in head dimensions or gross malformations of the surviving fetuses were detected at any time or concentration. Of all the parameters measured in this study none demonstrated a predilection for any specific period of major organogenesis. The results of this study indicate that while WR-2721 demonstrates a dose-related embryotoxicity it is not teratogenic.

Early changes accompanying development of adriamycin resistance in spheroids of a mouse mammary carcinoma line.

The early changes accompanying development of ADR resistance were studied in a mouse mammary adenocarcinoma cell line sensitive to ADR (S). Resistant cells (R) were derived from S by five separate exposures to 1 microgram/ml ADR for 1 hr. The R cells had a 3-fold increased resistance to ADR, a higher proportion of larger cells, higher numbers of chromosomes per cell and higher incidence of minute chromosomes. R spheroids had a higher degree of differentiation. They were more compact, had increased numbers of gap-junctions, and altered membranes. An inversion in the X chromosome in S cells was corrected in the R cells.

Comparison of cAMP with other radioprotectors against chronic damage to the rat parotid gland.

Radiation damage to the parotid gland is protectable by cAMP during the first week after irradiation (acute phase), though appreciable recovery occurred later with or without such protection. Further damage developed later (chronic phase, 60-90 days), and cAMP was still protective against this damage with a dose modification factor of 1.86 for gland weight. A summary of the protective factors, acute and chronic, for WR-2721, isoproterenol, and cAMP is included. Chronic damage is about 1.5 times as great as acute, and protection against acute and chronic damage is about equal for all three compounds.

Radioprotection of the rat parotid gland by cAMP.

Most earlier studies showing a radioprotective effect by cAMP show only slight degrees of protection. The present study demonstrates a substantial protective effect (DMF, 1.63) of exogenously administered cAMP on the rat parotid gland and supports the mechanism suggested previously for protection afforded the parotid glands by the beta-adrenergic agonist isoproterenol, which is known to elevate endogenous intracellular cAMP.

Radioprotection of the rat parotid gland by WR-2721 and isoproterenol and its modification by propranolol.

The aminothiol WR-2721 and beta-adrenergic agonist isoproterenol both conferred considerable radioprotection to the rat parotid gland. Isoproterenol acts on the beta-receptor, and its specific antagonist, propranolol, eliminated isoproterenol's protective effect, implicating the beta-receptor and possibly cAMP in the mechanism of the protection. Since other sulfhydryl-containing protectants have been shown to elevate cAMP it was reasoned that WR-2721 might do so as well. However, the radioprotection conferred by WR-2721 was not reduced by propranolol, showing that the beta-receptor played no part in WR-2721's action. The possible role of cAMP in radioprotection by isoproterenol is discussed.

Growth of mammalian multicellular tumor spheroids.

The in vitro growth of small (0.05 to 3 mm diameter) avascular multicellular tumor spheroids from six rodent and two human tumor lines has been analyzed. Surprisingly, the radial increase of multicellular tumor spheroids is linear with time after a brief initial period of geometric growth. These multicellular tumor spheroids are shown to have a constant thickness of proliferative outer crust and of middle nonproliferative but viable mantle. An analytical model for their growth is developed which explains the growth pattern. This constant crust thickness model leads to a progressively diminishing growth fraction as radius increases and should be applicable to such early growth of micrometastases in vivo. The model also provides a procedure for determining cell cycle time.

Ultrasonic effects on mammalian multicellular tumor spheroids.

Mammalian multicellular tumor spheroids (MTS), grown in liquid culture medium, 0.23 to 0.32 mm in diameter and consisting of 4,500 to 12,100 cells, were exposed to three ultrasonic machines: a clinical diagnostic device with an emitted intensity of 13 mW/cm2, a therapeutic machine with emitted intensities of 1 to 3.5 W/cm2, and a laboratory emitting 12 to 50 W/cm2. (All intensities are temporal and spatial average.) Four measures of ultrasonic effect on MTS were made: decrease in diameter after treatment, damage to subsequent growth outright kill, and number of cells detached from the MTS. There was no loss in MTS size from diagnostic or therapeutic exposures. None of the exposures from any of the three machines caused any damage to subsequent growth or survival. There was no significant detachment of cells from the MTS by any of the diagnostic exposures (at 13 mW/cm2, out of 40 minutes). With the laboratory machine, a significant number of cells were detached, about 0.02% of the MTS (approximately one cell per MTS) per W/cm2 in a ten-minute exposure. Cells detached by therapeutic exposure increased linearly with exposure. On the average, 1 W/cm2 detaches about 0.5 cells per minute, per MTS, or about 0.006% of the cells in the MTS.