Interferon-beta decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing-remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon-beta may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon-beta-1a on the expression of interleukin-10, a cytokine that strongly inhibits cell-mediated immune responses. Interferon-beta-1a induced accumulation of interleukin-10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon-beta-1a increased serum levels of interleukin-10 at 12 and 24 hours following the injection. Greater increases were induced with 12 x 10(6)-IU than 6 x 10(6)-IU injections. The effect of interferon-beta-1a was relatively specific for interleukin-10, as treatment with interferon-beta-1a did not result in accumulation of transforming growth factor-beta messenger RNA. Upregulation of interleukin-10 represents a possible mechanism of action of interferon-beta's therapeutic effect in relapsing-remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.

Recombinant interferon beta (IFNbeta) benefits patients with relapsing remitting multiple sclerosis (MS), but the mechanisms of action are unknown. We studied in vivo immunologic effects of IFNbeta treatment and their relationship to clinical efficacy. Cytokines were measured in blood and CSF from MS patients participating in a placebo-controlled phase III clinical trial and an open-label phase IV [corrected] tolerability study of IFNbeta-1a. Additionally, immunologic studies were conducted in animals with proteolipid protein (PLP)-induced chronic relapsing experimental autoimmune encephalomyelitis. Single intramuscular (IM) injections of IFNbeta-1a (6 MIU, 30 microg) were associated with significant in vivo upregulation of interleukin-10 (IL-10) and IL-4 but not IFNgamma mRNA in peripheral blood mononuclear cells. Forty-eight hours after each IFNbeta-1a injection, serum IL-10 levels increased and remained elevated for 1 week. IFNbeta-1a recipients in the placebo-controlled phase III clinical trial showed significantly increased concentrations of CSF IL-10 after 2 years of treatment. This response correlated with a favorable therapeutic response. Exposure of PLP-reactive murine T-cell lines to IFNbeta resulted in increased antigen-driven expression of IL-4 and IL-10 and reduced encephalitogenicity. IFNbeta-1a injections induce systemic and intrathecal immunosuppressive cytokines. Myelin-specific T cells treated with IFNbeta-1a demonstrate increased immunosuppressive cytokine expression and reduced encephalitogenicity. The relationship between increased CSF IL-10 and response to therapy suggests that induction of IL-10 is a mechanism underlying IFNbeta-1a effects in MS patients.

PurposeThe United States Medical Licensing Examination (USMLE) Step 1 plays a pivotal role in one’s residency application. While prior literature has investigated which factors influence performance on the examination, the authors sought to include factors such as performance on a well-used question bank and financial need to develop a predictive model.Method After obtaining institutional review board approval, the authors surveyed two consecutive second-year medical school classes and correlated the data to the students’ Step 1 and National Board of Medical Examiners (NBME) Comprehensive Basic Science Examination (CBSE) scores. The survey included questions such as how many days they studied per week, how many days they studied in total, which resources they used, how they performed on question banks, group studying habits, and whether they were receiving financial aid. The authors also assessed whether the students received only A letter grades during the first year of medical school. The authors used SPSS® Statistics V22.0 (IBM® Corporation, NY, USA ) and included one-way analysis of covariance (ANOVA) and multiple linear regression for statistical analysis.Results Eighty-one students completed the survey with an average Step 1 score of 240.5 and with an average study time of 39.5 days. The Step 1 Scores significantly correlated with the CBSE taken immediately preceding the dedicated study period (r=0.711, P=<0.001), UWorld Question Bank (UWorld) percentage correct (r = 0.622, P<0.001), straight As during first-year (r=0.356, P=0.001), and financial need (r=0.318, P=0.01). The scores were not correlated with age, gender, Medical College Admissions Test (MCAT), prior medical training, number of days studied, or the students’ perception of appropriate time studied. The authors developed a predictive model accounting for 62.3% of the variability. 140.625+(0.319xCBSE)-(3.817xA)+(5.845xN)+(0.452xU), where A=1 if straight As, N=1 if receiving need-based scholarship, U=UWorld percent-correct, and CBSE=the three-digit score of the CBSE taken prior to the dedicated study period.Conclusions Academic performance and financial need may predict Step 1 scores. Interestingly, the number of days studied did not have a correlation with scores, suggesting that increased length of study may not ameliorate poor grades.

Ovarian follicular development was analyzed in intact and unilaterally ovariectomized cyclic rats. Holtzman rats, followed for three successive cycles, were classified as 4-or 5-day animals, with estrus designated as day 1. Intact 4-and 5-day animals were killed on each day of the estrous cycle and one ovary from each animal was saved for histology and examined for normal follicles larger than 352 p, Cycling rats were unilaterally ovariectomized on day 1 and killed on each of the remaining days of the immediate estrous cycle and day 1 of the next cycle. The follicular population (normal follicles larger than 352 p ) was studied in the remaining ovary.During the estrous cycle of intact rats, there was a gradual increase in the number of follicles with a diameter of 518 to 571 p and greater; however, the totaI number of follicles ranging in size from 352 to 571 p and larger remained relatively constant. At day 5, in the 5-day cycling rat, the ovaries were depleted of follicles measuring from 395 to 570 p.Following unilateral ovariectomy on day 1, there was a temporary decrease in the number of follicles larger than 448 p. This agreed with the finding that animals semi-spayed on day 1 and injected with 20 I.U. human chorionic gonadotropin on day 2 (PM) did not ovulate, whereas intact animals ovulated an average of seven eggs after the same treatment. The remaining ovary of animals unilaterally ovariectomized on day 1 showed a significant increase by the next estrus in the number of follicles larger than 448 p.The method of compensatory ovulation in the rat involved doubling the number of large follicles which ultimately matured during the estrous cycle. This resulted from increased proliferation of smaller follicles in the course of the cycle rather than from decreased follicular atresia.

In the present study, we describe the innovative use of the National Board of Medical Examiners (NBME) Comprehensive Basic Science Examination (CBSE) as a progress test during the preclerkship medical curriculum. The main aim of this study was to provide external validation of internally developed multiple-choice assessments in a new medical school. The CBSE is a practice exam for the United States Medical Licensing Examination (USMLE) Step 1 and is purchased directly from the NBME. We administered the CBSE five times during the first 2 yr of medical school. Student scores were compared with scores on newly created internal summative exams and to the USMLE Step 1. Significant correlations were observed between almost all our internal exams and CBSE scores over time as well as with USMLE Step 1 scores. The strength of correlations of internal exams to the CBSE and USMLE Step 1 broadly increased over time during the curriculum. Student scores on courses that have strong emphasis on physiology and pathophysiology correlated particularly well with USMLE Step 1 scores. Student progress, as measured by the CBSE, was found to be linear across time, and test performance fell behind the anticipated level by the end of the formal curriculum. These findings are discussed with respect to student learning behaviors. In conclusion, the CBSE was found to have good utility as a progress test and provided external validation of our new internally developed multiple-choice assessments. The data also provide performance benchmarks both for our future students to formatively assess their own progress and for other medical schools to compare learning progression patterns in different curricular models.