OBJECTIVES:Positron emission tomography (PET) studies have shown that cortical cerebral metabolic rate of glucose (CMRglc) is reduced in multiple sclerosis (MS). Quantitative magnetic resonance spectroscopy (MRS) measures of N-acetyl-aspartate (NAA) normalized to creatine (NAA/Cr) assess neuronal deterioration, and several studies have shown reductions in MS. Furthermore, both PET and MRS reductions correlate with cognitive dysfunction in MS. Our aim was to determine if changes in cortical CMRglc in early MS correlate with NAA/Cr measurements of neuronal deterioration, as well as cognitive dysfunction and neurological disability.METHODS:We studied 20 recently diagnosed, clinically definite, relapsing-remitting MS patients. Global and cortical CMRglc was estimated using PET with 18-F-deoxyglucose and NAA/Cr ratio was measured using multislice echo-planar spectroscopic imaging. All subjects were neuro-psychologically tested and a cognitive dysfunction factor (CDF) was calculated.RESULTS:Cortical CMRglc correlated with cortical NAA/Cr (r = 0.45; P < 0.05), but there were no correlation between CMRglc and other NAA/Cr measurements, conventional magnetic resonance imaging measurements, or CDF. Stepwise regression analysis showed association between cortical NAA/Cr and CMRglc of the left ventrolateral prefrontal cortex (P < 0.001), left putamen (P = 0.010), and left hippocampus (P = 0.011). Furthermore, CDF was related to CMRglc in the left cerebellum (P = 0.001) and the left caudate nucleus (P = 0.013). The results of the statistical analysis should be regarded as exploratory, since we did not correct for multiple comparisons.CONCLUSION:Our findings suggest that reductions in cortical CMRglc are associated with reductions in cortical NAA/Cr in early MS. These changes affect cortical and subcortical neural circuits of importance to cognitive function.

We measured neutralizing antibodies (NABs) and the in vivo biologic response to interferon-beta on neopterin and beta(2)-microglobulin blood levels. All NAB-negative patients had an in vivo biologic response (full or partial), whereas all high-level positive patients had no response. High-level NAB patients had more MRI activity than NAB-negative patients (p = 0.031). Patients with a full response had less MRI activity than patients without biologic response (p = 0.032).

Background: Whole-brain N-acetyl aspartate (NAA), a measure of neuronal function, can be assessed by multislice echo-planar spectroscopic imaging.Objective: To test the hypothesis that the global brain NAA/creatine (Cr) ratio is a better predictor of cognitive dysfunction in multiple sclerosis than conventional magnetic resonance imaging measures.Design: Survey.Setting: Research-oriented hospitalsPatients: Twenty patients, 16 women and 4 men (mean age, 36 years), with early relapsing-remitting multiple sclerosis (mean Expanded Disability Status Scale score, 2.5).Main Outcome Measures: Correlation between the global NAA/Cr ratio and a cognitive dysfunction factor comprising 16 measures from an extensive neuropsychological test battery that best distinguished patients with multiple sclerosis from healthy control subjects.Results: A significant partial correlation between the global NAA/Cr ratio and the cognitive dysfunction factor was found (partial r = 0.62, P = .01), and 9 cognitively impaired patients had significantly lower global NAA/Cr ratios than 11 unimpaired patients (P = .04). No significant correlations were found between the cognitive dysfunction factor and conventional magnetic resonance imaging measures (ie, brain parenchymal fraction and lesion volume).Conclusions: Multislice echo-planar spectroscopic imaging provides global metabolic measures that distinguish between cognitively impaired and unimpaired patients with multiple sclerosis and correlate with a global cognitive measure. Standardization of the technique is needed, and larger-scale studies that include healthy controls are suggested.

Cognitive impairment occurs in early multiple sclerosis (MS), may decline over time, and has major impact on social functioning. The objectives of this study were to examine cognitive functioning in newly diagnosed MS, and to follow up over a period of 5 years. The results of the first three yearly re-examinations are reported. Eighty newly diagnosed (<1 year) MS patients participated (male/female: 19:61, mean age: 35 years, mean EDSS 2.7, course: 75 relapsing-remitting, 3 primary progressive, 2 secondary progressive). Seventy-five healthy persons served as controls. The neuropsychological (NP) test battery comprised 30 test measures and was grouped into seven cognitive domains. A residual score of -1.5 SD as cut-off point was used to diagnose cognitive impairment. At the first examination, 44-48% had cognitive impairment. None of the patients were clinically depressed, 51% had no signs of depression on Beck Depression Inventory (BDI), and none had severe signs. Sixty-four patients completed four examinations, and a significant linear improvement over time was seen in three cognitive domains, no change in two domains, and deterioration in one domain. At the time of the fourth examination, 4.3 years since diagnosis, 33-34% of the patients had cognitive impairment. Thirty percent of the patients were on disablement pension, 34% received social services in relation to work and 13% had home care. Methodological problems are discussed, especially the practice effect and the importance of identifying sensitive and stable test measures.

MR spectroscopy (MRS) provides information about neuronal loss or dysfunction by measuring decreases in N‐acetyl aspartate (NAA), a metabolite widely believed to be a marker of neuronal viability. In multiple sclerosis (MS), whole‐brain NAA (WBNAA) has been suggested as a marker of disease progression and treatment efficacy in treatment trials, and the ability to measure NAA loss in specific brain regions early in the evolution of this disease may have prognostic value. Most spectroscopic studies to date have been limited to single voxels or nonlocalized measurements of WBNAA only, and longitudinal studies have often been hampered by standardization and reproducibility problems. Multi‐slice echo‐planar spectroscopic imaging (EPSI) is presented as a promising alternative to single‐voxel or nonlocalized spectroscopy for obtaining global metabolite estimates in MS. In the same session, measurements of metabolites in specific brain areas chosen after image acquisition (e.g., normal‐appearing white matter (NAWM), gray matter (GM), and lesions) can be obtained. The identification and exclusion of regions that are inadequate for spectroscopic evaluation in global assessments can significantly improve quality and reproducibility, as demonstrated by a low within‐subject variance in healthy controls. The reproducibility of the technique makes it a promising tool for future longitudinal spectroscopic studies of MS. Magn Reson Med 53:750–759, 2005. © 2005 Wiley‐Liss, Inc.

The epidemiology of Achilles tendon ruptures was examined during the 13-year period 1984-1996 in a Danish county. Five hospitals, serving a population of 220,000 cooperated. There were 718 ruptures, 544 men (75.8%) and 174 women (24.2%). The male to female ratio was 3:1. The average age was 42.1 years (3-82) and 62% were between 30-49 years. 74.2% of the ruptures were sport-related and 89% of these occurred in ball and racket games. The annual incidence of achilles tendon ruptures increased from 18.2/10(5) inhabitants in 1984 to 37.3/10(5) in 1996. The peak incidence in sport-related ruptures occurred in the age group 30-49 years, but ruptures not related to sport occurred in older patients with a peak incidence in those 50-59 years.

SUMMARY The data reviewed in this paper, suggest that besides their role in presentation of antigenic pcptides to T cells, MHC‐I molecules may play an important role in the fine‐tuning of signal transmission across the cell membrane by their associations with a variety of cell‐surface receptors regulating cell growth and differentiation.

We have studied activation-induced changes in intracellular calcium [Ca2+]i, interleukin-2 (IL-2) secretion, and clonal abortion of the human leukaemic T-cell line Jurkat and three T-cell receptor (TcR)/CD3 receptor negative clones deficient for the TcR alpha, TcR beta and CD3 gamma chains respectively, as well as three transfectant clones reconstituted with the appropriate TcR/CD3 cDNA. For activation, the cells were exposed to anti-TcR/CD3, anti-CD2 and anti-major histocompatibility complex (anti-MHC) class I monoclonal antibodies (mAb) respectively. Cellular activation by these mAb leading to an increased IL-2 secretion was preceded by a rise in [Ca2+]i and was relatively dependent on the expression of the a TcR/CD3 complex. In contrast, anti-MHC class I mAb-induced clonal abortion in Jurkat T cells may occur without previous fluctuations in [Ca2+]i and appeared to be independent of TcR/CD3 expression. The present observation suggest the existence of different secondary messenger systems operating in Jurkat cells following activation via the TcR/CD3, CD2 and the MHC class I pathways, respectively.

Young (H-2d, Ld+) severe combined immunodeficiency (scid) mice were injected intravenously with 10(5) CD4+CD8- T cells purified from spleen, thymus or lymph nodes (LN) of dm2 (H-2d, Ld-) donor mice. In the immunodeficient recipients, the lymphoid compartment in the splenic white pulp was repopulated with donor-type T cells and cellularity in the red pulp was increased. In addition, donor-type CD4+ T cells repopulated the peritoneal cavity, mesenteric LN and the lamina propria of the small intestine of scid mice, but were undetectable in thymus and peripheral (inguinal, axillary) LN. Histological examination of repopulated mesenteric LN showed expanded subcapsular sinuses, repopulated cortical areas, but poorly developed high endothelial venules (HEV) indicating deficient blood-LN lymphocyte recirculation. The engrafted CD4+ T cell population had the surface phenotype of memory T cells (CD44/Pgp-1high CD45RB(low) and expressed the Peyer's patch HEV-specific homing receptor CD49d (LPAM-1), but not the LN HEV-specific homing receptor LECAM-1. The CD4+ T cell population in spleen and mesenteric LN of transplanted scid mice displayed a diverse T cell receptor-V beta repertoire. Transfer of titrated numbers (10(3), 10(4), 10(5) cells per mouse) of CD4+ T cells into scid mice established donor-type T cell populations with this unusual homing pattern in all recipients. Repeated serial transfers of dm2 CD4+ T cells through young scid mice revealed an extensive in vivo expansion potential of transferred cells for > 18 months. The experimental system described represents an in vivo model to study the functional competence and the differentiation potential of a murine memory CD4+ T cell subset.

To evaluate the ability of thymic epithelial cells (TEC) to influence growth and differentiation of antigen specific T cells, we have used female transgenic (TG) mice expressing a receptor on the majority of their T cells for the male (H-Y) antigen in the context of H-2D(b) antigens. Male or female TEC expanded in serum-free medium were co-cultured with female TG thymocytes. FAC-Scan analysis after 3 days of co-culture did not indicate any selective deletion of subpopulations induced by male TEC. In contrast, the presence of TEC in TG thymocyte cultures led to increased proliferation, irrespective of the type of TEC and stimulus used. Limiting dilution (LD) proliferation analyses, using irradiated male spleen cells as stimulator cells, showed increased clonability of CD4-CD8+ cells, but reduced clonability of CD4-CD8+ thymocytes, in the presence of both male and female TEC. Clones from the LD cultures were expanded for several weeks. Expanded clones all expressed the vbeta8.2+ TG TCR. One-half of the expanded TG CD8+ T cell clones obtained from LD cultures exhibited H-Y specific proliferation, and the majority of clones showed antigen-specific IL-3 secretion. Expanded clones did not develop into a cytotoxic machinery in the present culture system.

Cells with veto activity induce a state of tolerance in T cell precursors with specificity for antigen determinants expressed on the surface of the veto-active cell. This state of tolerance is not strictly defined, but results in altered responses to specific antigen, such as decreased proliferation, decreased development of cytotoxicity and secretion of interleukins, down-regulated ability to reject grafts and expression of T cell and IL-2 receptors. Both clonal anergy and clonal deletion has been shown to operate in vetoed T cells. Veto-induced tolerance can be established in vitro and in vivo for both MHC class I and II as well as minor histocompatibility antigens. The most powerful veto activity is present in mature activated cytotoxic CD8+ T cells, but other cells including noncytotoxic cells are also capable of acting as veto cells. Thus it appears that veto activity per se is not confined to a certain cellular entity, but rather reflects a constitutively expressed immunoregulatory capability inherent to a broad array of activated T cell and non-T cell categories with their own distinct functions not related to their eventual veto activity.

Expression of CD4+ or CD8+ determinants and ten different TCR Vβ genes was analysed by two‐colour flow cytometry in lymph node cells (LNC) of BALB/c and dm2 (a BALB/c Ld loss mutant) mice. TCR Vβ14 expression of CD8+ T cells and TCR Vβ7 and 14 of CD4+ T Cells were significantly more frequent in BALB/c than in dm2 LNC, whereas no differences were observed in the frequency distribution of TCR Vβ+ CD4‐CD8‐ double negative LNC from BALB/c versus dm2 mice. These results represent the first published evidence for positive selection of particular TCR Vβ genes by individual MHC class I molecules in non‐manipulated mice.