Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract-induced Retinal Degeneration in F344/N Rats.

There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.

Reliability of a cognitive endpoint for use in a multiple sclerosis pharmaceutical trial.

OBJECTIVE: Determine reliability and basic psychometric properties of a composite cognitive endpoint, MS-COG, for monitoring change in cognitive function in MS drug trials. BACKGROUND: 50% of MS patients have cognitive impairment that impacts ability to work and quality of life. We selected neuropsychological tests based on sensitivity to MS cognitive impairment, availability of alternate forms, cross-cultural utility, and feasibility for multicenter trials, and assessed the reliability and validity of a composite endpoint, MS-COG. DESIGN/METHODS: Administered SRT, BVMT-R, PASAT, and SDMT to 60 MS patients at 4 US centers twice over 45days, along with symptom inventories by patients and informants. RESULTS: The MS-COG had test-retest reliability of 0.91. Processing Speed and Memory indices had reliabilities of 0.89 and 0.86, with modest practice effects. Reliability was high for the RR MS and SP MS subgroups as well, with correlations of .90 and .93, respectively for MS-COG. Overall, 42% of subjects obtained MS-COG scores in the impaired range, with SP MS subjects performing 0.8 SD below RR MS subjects. Impairment correlated well (r=0.37 to 0.40) with informant reports but was inconsistent with patient report, with the least reliable assessments by those with greater symptom severity. CONCLUSIONS: The MS-COG is a reliable, repeatable measure of MS cognitive functioning that is sensitive to cognitive impairment in SP MS and RR MS patients and feasible for multicenter clinical trials. Further development is warranted.

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).

BACKGROUND: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. OBJECTIVE: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. METHODS: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. RESULTS: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test - Second Edition and the Brief Visuospatial Memory Test - Revised learning trials if a further 10 minutes could be allocated for testing. CONCLUSIONS: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

The relationship between subjective reports of fatigue and executive control in multiple sclerosis.

UNLABELLED: Previous studies failed to show a relationship between fatigue and cognitive performance. We used a theory-based Delayed Item Recognition (DIR) paradigm to examine the hypothesis that subjective reports of fatigue and executive control processes were related in MS. Participants were 20 individuals diagnosed with definite diagnosis of MS with Relapsing-Remitting course and 20 controls case matched for age, sex, education and IQ. The DIR paradigm manipulated executive demands in three conditions: Alone, Partial Interference (PI), and Complete Interference (CI). Fatigue was assessed using the Fatigue Severity Scale (FSS). RESULTS: ANOVA Repeated measures analyses showed that DIR performance was slower and less accurate as a function of MS and increased executive demands across the three task conditions. Separate linear regressions revealed that fatigue was related to DIR reaction time and accuracy performance only in the CI condition where executive demands are maximized, and only in the MS group. The present study provided first behavioral evidence that fatigue and executive control are uniquely related in MS.

Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire.

Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Questionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. Analyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. Cronbach's alpha coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.

Rehabilitation of intimacy and sexual dysfunction in couples with multiple sclerosis.

Sexual dysfunction is a highly prevalent symptom of multiple sclerosis (MS), with little published research on effective treatments. This pilot study tested the efficacy of a counseling intervention in nine couples utilizing a quasi-experimental research design. The intervention consisted of 12 counseling sessions, communication with the MS medical treatment team, education, and tailoring symptomatic treatments so they interfere less with sexual function. Repeated measures analysis of variance indicated significant improvements in affective and problem-solving communication, marital satisfaction, and sexual satisfaction during the treatment vs. the waiting list phase of the study (F=1.7, P<.001). MS patients and their spouses reported similar levels of improvement.

Stress and course of disease in multiple sclerosis.

In this prospective study, 96 healthy controls and 101 multiple sclerosis patients were followed up for as many as 6 years, and self-reported stressful events and health status were assessed. The authors evaluated (a) whether patients reported more stressful life events than healthy controls and (b) the bidirectional relationship between stress and functional deterioration among patients. Healthy controls reported more life events than patients, Odds ratio (OR) = 1.13, p < .0001; and this relationship was attributable to healthy controls' reporting more neutral/positive events than patients. A bidirectional relationship was confirmed between stress and illness: there was an increased risk of disease progression when rate of reported stressful events was higher, OR = 1.13, p < .0003, and an increased risk of reported stressful events when rate of disease progression was higher, OR = 2.13, p < .0001. There were no differences in reported stress by level of baseline disability. The authors concluded that multiple sclerosis patients demonstrate a vicious cycle between stress and disease progression.

Helplessness, self-efficacy, cognitive distortions, and depression in multiple sclerosis and spinal cord injury.

The aim of this study was to determine if learned helplessness, self-efficacy, and cognitive distortions would predict depression in a sample of 80 individuals with multiple sclerosis (MS) and 80 individuals with a spinal cord injury (SCI). As MS and SCI usually present with disparate disease courses and etiologies, a secondary objective was to determine if individuals with MS would exhibit greater levels of helplessness, cognitive distortions, and depression and lower levels of self-efficacy than those with SCI. Results indicated that helplessness and self-efficacy significantly predicted depression for both the MS and SCI groups after controlling for confounding variables. Cognitive distortions had no independent effect, indicating that cognitive distortions may have caused feelings of helplessness and low self-efficacy and, in this way, had indirect effects on depression. The MS group exhibited significantly greater levels of depression and helplessness and significantly lower levels of self-efficacy than the SCI group. It was hypothesized that it may have been the combination of an unpredictable course of disease activity and the possibility of being affected by MS in many different ways that produced greater feelings of depression, helplessness, and low self-efficacy in the MS group.

Psychosocial, Affective, and Behavioral Consequences of Multiple SclerosisTreatment of the "Whole" Patient.

Multiple sclerosis (MS) challenges the individual, the family, and society because (1) it can produce wide-ranging functional losses; (2) it is generally progressive with functional losses increasing over time; and (3) its course is unpredictable. Persons affected by MS respond by (1) experiencing changes in their perception of themselves and their world; (2) altering their social roles; and (3) undergoing a variety of emotional responses, especially depression and grief over the losses caused by the illness. Psychosocial interventions that address MS challenges include (1) educational interventions such as lectures, workshops, and books; (2) supportive interventions such as counseling and support groups; (3) psychoeducational interventions such as communication skills training; and (4) somatic therapies such as antidepressants. The unpredictable and progressive course of MS means that affected individuals face a lifetime of periodic challenge. Comprehensive care in MS must address the psychosocial challenges of the illness on a long-term basis. In this way MS care can address the whole patient.

Stress, Multiple Sclerosis, and Everyday FunctioningA Review of the Literature with Implications for Intervention.

Numerous studies have described an association between stress and the onset or exacerbation of multiple sclerosis (MS). Most of the studies that have been conducted to date, however, have had methodological flaws including: (1) retrospective designs, (2) inadequate or absent control groups, (3) small sample sizes, (4) clinical measures that are insensitive to underlying disease activity, and (5) wide variation in the measurement of stress. Animal models of MS have enabled researchers to examine the effects of stress directly in the central nervous system. Stress affects three biological systems that may be dysregulated in MS: the neuroendocrine system, the sympathetic nervous system, and the serotonergic neurotransmitter system. Future stress-MS research should evaluate the relationship between stress and these systems.

A prospective study of depression and immune dysregulation in multiple sclerosis.

This study examined psychologic distress and immune function in patients with chronic-progressive multiple sclerosis participating in a placebo-control trial of cyclosporine. Immune measures included percentages and absolute numbers of CD2+, CD4+, CD8+, Leu-11-b+, HLA-DR (IA+), and transferrin-receptor-positive cells, which were evaluated by immunofluorescence using monoclonal antibodies. Distress was measured with self-report scales. The Expanded Disability Status Scale assessed neurologic disability. Subjects were followed up for 2 years, and their high-depressed and low-depressed times were compared. Times of greater depression were associated with lower CD8+ cell numbers and CD8+%, and a higher CD4/CD8 ratio. CD4+ cell numbers and percent were also higher when subjects were depressed, but only in the placebo group. There were no differences in Expanded Disability Status Scale when subjects were more depressed. Evaluation of a single subject revealed that Ia+ and transferrin-receptor-positive lymphocytes increased 3 months before distress increased. It was concluded that distress is associated with immune dysregulation in multiple sclerosis, although the mechanisms of this association have yet to be delineated.

Development of a structured interview to accompany the minimal record.

In conjunction with field trials of the Minimal Record of Disability in MS, a Structured Interview was developed. The purpose of this effort was to achieve some standardization in the methods used for gathering the information needed to rate the items on the MRD. Since the Impairment portion of the MRD is based on the neurological examination, a reasonably standard procedure, the focus of the SI was only on Incapacity and Environmental Status. Following a review of existing functional assessment instruments, questions were constructed to match the items on the ISS and ESS. These questions were piloted with a small group of patients and revised. The ISS was utilized in the field trials of the MRD in the U.S. and Canada. Based upon experience in that study extensive revisions were made in the SI. These revisions reflect new items added to the MRD, items retained but revised, clarification of wording in the interview, and simplification of the interview format.

Demonstration of multiple antigenic sites of the SV40 transplantation rejection antigen by using cytotoxic T lymphocyte clones.

Multiple antigenic sites on the simian virus 40 (SV40) tumor-specific transplantation antigen (TSTA) were detected by the use of cytotoxic T lymphocyte (CTL) clones isolated from continuous cultures of SV40-specific CTL (H-2b). Two independently derived clones, K11 and K19, specific for the SV40 TSTA in association with H-2Db, each recognized a different antigenic determinant of the SV40 TSTA. This conclusion was based on the observation that a human papovavirus BK virus (BKV) transformed cell line, which possesses a T antigen serologically cross-reactive with that of SV40, was lysed by a heterogeneous population of SV40-immune lymphocytes and by clone K19 but not by K11. Therefore, these CTL clones must recognize two different antigenic determinants of the SV40 TSTA:K19 recognizes a cross-reactive determinant of the SV40 and BKV TSTA, whereas K11 is reactive against an SV40-specific determinant.

Histochemical study of gastric mucosubstances after thermal injury: correlation with endoscopic evidence of acute gastroduodenal disease.

Gastroduodenoscopy with biopsy was performed in nine patients within 5 days after major thermal injury. Biopsies were evaluated by special histochemical techniques to visualize and differentiate cellular mucosubstances. Acute gastroduodenal lesions were encountered early and frequently in 78% of adult burn patients. The early occurrence, morphology, and histology of these lesions suggest that alterations in gastric mucosal blood flow may play an important etiologic role. A decreased production of gastric mucus does not appear to be an etiologic factor since acute gastric mucosal disease was encountered in most patients despite normal quantities of cellular mucosubstances.