Sensitive Detection of Infratentorial and Upper Cervical Cord Lesions in Multiple Sclerosis with Combined 3D FLAIR and T2-Weighted (FLAIR3) Imaging.

BACKGROUND AND PURPOSE: Infratentorial and spinal cord lesions are important for diagnosing and monitoring multiple sclerosis, but they are difficult to detect on conventional MR imaging. We sought to improve the detection of infratentorial and upper cervical cord lesions using composite FLAIR3 images. MATERIALS AND METHODS: 3D T2-weighted FLAIR and 3D T2-weighted images were acquired in 30 patients with MS and combined using the FLAIR3 formula. FLAIR3 was assessed against 3D T2-FLAIR by comparing the number of infratentorial and upper cervical cord lesions per subject using the Wilcoxon signed rank test. Intrarater and interrater reliability was evaluated using the intraclass correlation coefficient. The number of patients with and without ≥1 visible infratentorial/spinal cord lesion on 3D T2-FLAIR versus FLAIR3 was calculated to assess the potential impact on the revised MS diagnostic criteria. RESULTS: Compared with 3D T2-FLAIR, FLAIR3 detected significantly more infratentorial (mean, 4.6 ± 3.6 versus 2.0 ± 1.8, P < .001) and cervical cord (mean, 1.58 ± 0.94 versus 0.46 ± 0.45, P < .001) lesions per subject. FLAIR3 demonstrated significantly improved interrater reliability (intraclass correlation coefficient = 0.77 [95% CI, 0.63-0.87] versus 0.60 [95% CI, 0.40-0.76] with 3D T2-FLAIR, P = .019) and a tendency toward a higher intrarater reliability (0.86 [95% CI, 0.73-0.93] versus 0.79 [95% CI, 0.61-0.89], P = .23). In our cohort, 20%-30% (47%-67%) of the subjects with MS had ≥ 1 infratentorial (cervical cord) lesion visible only on FLAIR3. CONCLUSIONS: FLAIR3 provides higher sensitivity than T2-FLAIR for the detection of MS lesions in infratentorial brain parenchyma and the upper cervical cord.

Antivirus immune activity in multiple sclerosis correlates with MRI activity.

OBJECTIVE: The objective of this study was to determine whether reactivation of Epstein-Barr (EBV) or activation of the anti-EBV immune response correlates with MS disease activity on MR imaging. METHODS: Subjects with early, active relapsing-remitting MS were studied for 16 weeks with blood and saliva samples collected every 2 weeks and brain MRI performed every 4 weeks. We isolated peripheral blood mononuclear cells from each blood sample and tested the immune response to EBV, autologous EBV-infected lymphoblastoid cell lines (LCL), human herpesvirus 6 (HHV6), varicella zoster virus (VZV), tetanus, and mitogens. We measured the proliferative response and the number of interferon-γ secreting cells with ELISPOT. We measured the amounts of EBV, HHV6, and VZV DNA in blood and saliva with quantitative PCR. On MRI, we measured number and volume of contrast enhancing and T2 lesions. We tested for correlation between the immunologic assays and the MRI results, assessing different time intervals between the MRI and immunologic assays. RESULTS: We studied 20 subjects. Ten had enhancing lesions on one or more MRI scans and one had new T2 lesions without enhancement. The most significant correlation was between proliferation to autologous LCL and the number of combined unique active lesions on MRI 4 weeks later. Both proliferation and number of cells secreting interferon-γ in response to LCL correlated with the number of enhancing lesions 8 weeks later. CONCLUSIONS: We find evidence for correlation of antiviral immune responses in the blood with subsequent disease activity on MRI scans.

New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.

BACKGROUND: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. METHODS: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon beta-1b (IFNbeta1b) in the BECOME study. FINDINGS: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for >or=1 year, 103 (18.8%) were still visible >or=12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up >or=1 year converted to CBH, 9.8% with IFNbeta1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNbeta1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. INTERPRETATION: Only a minority of new brain lesions in patients with MS treated with GA or IFNbeta1b convert to CBH.

Enzymatically inactive eosinophil peroxidase inhibits proinflammatory cytokine transcription and secretion by macrophages.

The present investigators have reported previously that macrophages (Mphi) can bind either myeloperoxidase (MPO) or eosinophil peroxidase (EPO) resulting in enhanced cytotoxicity to Candida albicans. Since MPO was shown to be immunomodulatory, the present study was initiated to determine whether either EPO or partially fragmented EPO (fgEPO) also modulated cytokine secretion. Murine peritoneal Mφ simultaneously stimulated with fgEPO and one of the following, (1) LPS, (2) mannosylated bovine serum albumin (mBSA), (3) interferon-gamma (IFN-gamma), or (4) Poly I:C, demonstrated both dose- and time-dependent decreases in TNF-alpha and IL-6 and a dose-dependent decrease in IFN-alpha/beta. The mRNA levels of Mphi exposed to fgEPO and mBSA demonstrated that fgEPO modulated Mphi cytokine function by decreasing TNF-alpha and IL-6 mRNA transcripts without altering transcription of TGF-beta or GM-CSF. These results demonstrate a possible interaction between the Mphi and eosinophil that could result in reduction of inflammation.

Macrophage-mediated candidacidal activity is augmented by exposure to eosinophil peroxidase: a paradigm for eosinophil-macrophage interaction.

Various disease states are associated with eosinophilia and the release of eosinophil peroxidase (EPO) into the microenvironment. The present study targets the effects of low levels of EPO on macrophage (M phi) phagocytosis and intracellular killing of Candida albicans as well as M phi oxidative activity measured as the luminescence product of luminol dioxygenation. Resident murine peritoneal M phi were exposed to various concentrations of EPO. Chemiluminescence data indicate that nanomolar concentrations of EPO markedly enhanced the dioxygenation activity (respiratory burst) of M phi. In other studies, the exposure of M phi to 0.17 microM EPO for 10 min. enhanced M phi-mediated candidacidal activity 10 fold. The above data indicate that EPO enhances certain M phi functions. Also the results illustrate a previously un-recognized interaction between eosinophils and M phi and implicate yet another possible role for EPO in host defenses against disease.

Enhancement of macrophage-mediated bactericidal activity by macrophage-mannose receptor-ligand interaction.

Neutrophils represent one of the host's primary defenses against invading organisms. These cells often arrive at the site of infection prior to macrophages (M phi). Neutrophils release myeloperoxidase (MPO) into the micro-environment during phagocytosis. Previous studies by the present investigators have shown that M phi bactericidal activity is enhanced by exposure to MPO. A recent report suggests that as much as 40% of this protein is enzymatically inactive once it is released into the micro-environment. In the present study, exposure of M phi to an enzymatically inactive form of MPO (iMPO) or another mannosylated protein, mannosylated bovine serum albumin (mBSA), can induce the same enhanced Mø-mediated bacterial cell killing observed with the active form of MPO. Furthermore, this phenomenon is limited as galactosylated BSA (gBSA) did not induce enhancement of bacterial killing. The data suggest that interaction of either enzymatically active or inactive mannosylated proteins with the M phi mannose receptor (MMR), is sufficient to enhance M phi bactericidal activity and further underscores the binding of the MMR and resultant responses as a major host defense mechanism.

Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan.

Previous studies by these investigators have shown that mannosylated bovine serum albumin (m-BSA) enhances the respiratory burst (RB), phagocytosis, and killing of Candida albicans by resident murine peritoneal macrophages (MO). Upregulation of the above MO functions was associated with binding of m-BSA to the MO-mannose receptor. The present study was done to determine if the immunostimulant, acemannan prepared from aloe vera, could stimulate MO in a similar manner. Resident peritoneal MO collected from C57BL/6 mice were exposed to acemannan for 10 min. The RB was measured using chemiluminescence and demonstrated approximately a two-fold increase above the media controls. In studies involving phagocytosis, MO were exposed to acemannan, washed and exposed to Candida at a ratio of 1:5. The percent phagocytosis and Candida killing were determined using fluorescence microscopy. There was a marked increase in phagocytosis in the treated cultures (45%) compared to controls (25%). Macrophages exposed to acemannan for 10 min resulted in ca 38% killing of Candida albicans compared with 0-5% killing in controls. If MO were incubated with acemannan for 60 min, 98% of the yeast were killed compared to 0-5% in the controls. The results of the present study indicate that short term exposure of MO to acemannan upregulates the RB, phagocytosis and candidicidal activity. Further studies are needed to clarify the potential use of this immunostimulant as an anti-fungal agent.

Exogenous myeloperoxidase enhances bacterial phagocytosis and intracellular killing by macrophages.

It is well documented that myeloperoxidase (MyPo) contributes to the bacterial activities of neutrophils and monocytes. Since mature macrophages (M phi) are devoid of this enzyme, its participation in M phi-mediated phagocytes and bacterial killing has not been completely defined. The present study demonstrates the exogenously added MyPo, at physiological levels, enhances both phagocytosis and killing of Escherichia coli. Murine peritoneal M phi were exposed to various concentrations of MyPo for different time intervals. Viable opsonized E. coli was added either prior to or after addition of MyPo. Thioglycolate-induced but not resident M pho exhibited an increase in the number of phagocytizing cells. Both resident and thioglycolate-induced M phi demonstrated increased bactericidal activity. Physiological levels of soluble MyPo also induced a significant increase in chemiluminescence. Since luminol-dependent chemiluminescence measures reactive oxygen intermediate production, studies were done to determine whether superoxide anion or H2O2 was involved in MyPo-induced M pho killing. Both superoxide dismutase and catalase ablated MyPo-induced bactericidal activity. The above data suggest that soluble MyPo, released from neutrophils at a site of infection or inflammation, can enhance both phagocytosis and killing of microorganisms.

Selecting a few residents from many applicants: a new way to be fair and efficient.

Selection of residents from among the large number of qualified applicants is an annual task requiring a significant commitment of resources by teaching hospitals. A method based on sound principles of decision-making and utilizing a computer analysis for initial ranking of applicants was developed to improve the selection process. The result was satisfactory selection with significant savings of time and effort for the residency program faculty.