Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs.

Phosphate mono- and diesters can be liberated efficiently from boryl allyloxy (BAO) and related phosphotriesters by H2O2. This protocol was applied to the release of a phosphorylated serine derivative and the nucleotide analogue AZT monophosphate. Nucleotide release in the presence of ATP and a kinase provides a diphosphate, demonstrating that this method can be applied to biological processes.

Open Preperitoneal Inguinal Hernia Repair, TREPP Versus TIPP in a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to compare chronic postoperative inguinal pain (CPIP) in patients with an inguinal hernia after the TransREctus Sheath PrePeritoneal (TREPP) and the TransInguinal PrePeritoneal Technique (TIPP). BACKGROUND: The preperitoneal mesh position for inguinal hernia repair showed beneficial results regarding CPIP with low recurrence rates. Two open preperitoneal techniques, TREPP and TIPP, were compared in a randomized clinical trial with the hypothesis of fewer patients with CPIP after TREPP due to complete avoidance of nerve contact. METHODS: Adult patients with a primary unilateral inguinal hernia were randomized to either TREPP or TIPP in four hospitals. Before the trial's start the study protocol was ethically approved and published. Outcomes included CPIP after 1 year (primary outcome) and recurrence rates, adverse events, and health-related quality of life (secondary outcomes). Follow-up was performed at 2 weeks, 6 months, and 1 year. RESULTS: Baseline characteristics were comparable in both groups. Pain was less often present after TREPP at 2 weeks and 6 months, but CPIP at rest at 1 year was comparable: 1.9% after TREPP vs 1.4% after TIPP, P = 0.535). The overall recurrence rate was higher in the TREPP group, 8.9% vs 4.6%, P = 0.022). Corrected for a learning curve for TREPP, no significant difference could be assessed (TREPP 5.7% and TIPP 4.8%, P = 0.591). CONCLUSION: Both the TREPP and TIPP technique resulted in a low incidence of CPIP after 1-year follow-up. The TREPP method can be considered a solid method for inguinal hernia repair if expertise is present. The learning curve of the TREPP techniques needs further evaluation. TRIAL REGISTRATION: ISRCTN18591339.

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases.

BACKGROUND: Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties. METHODS: Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. RESULTS: A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. CONCLUSIONS: Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention.

Live predator stress in adolescence results in distinct adult behavioral consequences and dorsal diencephalic brain activation patterns.

Exposure to traumatic events during childhood increases the risk of adult psychopathology, including anxiety, depression, alcohol use disorders and their co-morbidity. Early life trauma also results in increased symptom complexity, treatment resistance and poor treatment outcomes. The purpose of this study was to establish a novel rodent model of adolescent stress, based on an ethologically relevant life-threatening event, live predator exposure. Rats were exposed to a live predator for 10 min. at three different time points (postnatal day (PND)31, 46 and 61). Adult depression-, anxiety-like behaviors and ethanol consumption were characterized well past the last acute stress event (two weeks). Behavioral profiles across assessments were developed to characterize individual response to adolescent stress. CNS activation patterns in separate groups of subjects were characterized after the early (PND31) and last predator exposure (PND61). Subjects exposed to live-predator adolescent stress generally exhibited less exploratory behavior, less propensity to venture into open spaces, a decreased preference for sweet solutions and decreased ethanol consumption in a two-bottle preference test. Additional studies demonstrated blunted cortisol response and CNS activation patterns suggestive of habenula, rostromedial tegmental (RMTg), dorsal raphe and central amygdala involvement in mediating the adult consequences of adolescent stress. Thus, adolescent stress in the form of live-predator exposure results in significant adult behavioral and neurobiological disturbances. Childhood trauma, its impact on neurodevelopment and the subsequent development of mood disorders is a pervasive theme in mental illness. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies.

Coding and long non-coding RNAs provide evidence of distinct transcriptional reprogramming for two ecotypes of the extremophile plant Eutrema salsugineum undergoing water deficit stress.

BACKGROUND: The severity and frequency of drought has increased around the globe, creating challenges in ensuring food security for a growing world population. As a consequence, improving water use efficiency by crops has become an important objective for crop improvement. Some wild crop relatives have adapted to extreme osmotic stresses and can provide valuable insights into traits and genetic signatures that can guide efforts to improve crop tolerance to water deficits. Eutrema salsugineum, a close relative of many cruciferous crops, is a halophytic plant and extremophyte model for abiotic stress research. RESULTS: Using comparative transcriptomics, we show that two E. salsugineum ecotypes display significantly different transcriptional responses towards a two-stage drought treatment. Even before visibly wilting, water deficit led to the differential expression of almost 1,100 genes for an ecotype from the semi-arid, sub-arctic Yukon, Canada, but only 63 genes for an ecotype from the semi-tropical, monsoonal, Shandong, China. After recovery and a second drought treatment, about 5,000 differentially expressed genes were detected in Shandong plants versus 1,900 genes in Yukon plants. Only 13 genes displayed similar drought-responsive patterns for both ecotypes. We detected 1,007 long non-protein coding RNAs (lncRNAs), 8% were only expressed in stress-treated plants, a surprising outcome given the documented association between lncRNA expression and stress. Co-expression network analysis of the transcriptomes identified eight gene clusters where at least half of the genes in each cluster were differentially expressed. While many gene clusters were correlated to drought treatments, only a single cluster significantly correlated to drought exposure in both ecotypes. CONCLUSION: Extensive, ecotype-specific transcriptional reprogramming with drought was unexpected given that both ecotypes are adapted to saline habitats providing persistent exposure to osmotic stress. This ecotype-specific response would have escaped notice had we used a single exposure to water deficit. Finally, the apparent capacity to improve tolerance and growth after a drought episode represents an important adaptive trait for a plant that thrives under semi-arid Yukon conditions, and may be similarly advantageous for crop species experiencing stresses attributed to climate change.

Accurate Patient-Specific Machine Learning Models of Glioblastoma Invasion Using Transfer Learning.

BACKGROUND AND PURPOSE: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data. MATERIALS AND METHODS: We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS: Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS: Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.

Retrospective Validation of a Computer-Assisted Quantification Model of Intracerebral Hemorrhage Volume on Accuracy, Precision, and Acquisition Time, Compared with Standard ABC/2 Manual Volume Calculation.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage accounts for 6.5%-19.6% of all acute strokes. Initial intracerebral hemorrhage volume and expansion are both independent predictors of clinical outcomes and mortality. Therefore, a rapid, unbiased, and precise measurement of intracerebral hemorrhage volume is a key component of clinical management. The most commonly used method, ABC/2, results in overestimation. We developed an interactive segmentation program, SegTool, using a novel graphic processing unit, level set algorithm. Until now, the speed, bias, and precision of SegTool had not been validated. MATERIALS AND METHODS: In a single stroke academic center, 2 vascular neurologists and 2 neuroradiologists independently performed a test-retest experiment that involved repeat measurements of static, unchanging intracerebral hemorrhage volumes on CT from 76 intracerebral hemorrhage cases. Measurements were made with SegTool and ABC/2. True intracerebral hemorrhage volumes were estimated from a consensus of repeat manual tracings by 2 operators. These data allowed us to estimate measurement bias, precision, and speed. RESULTS: The measurements with SegTool were not significantly different from the true intracerebral hemorrhage volumes, while ABC/2 overestimated volume by 45%. The interrater measurement variability with SegTool was 50% less than that with ABC/2. The average measurement times for ABC/2 and SegTool were 35.7 and 44.6 seconds, respectively. CONCLUSIONS: SegTool appears to have attributes superior to ABC/2 in terms of accuracy and interrater reliability with a 9-second delay in measurement time (on average); hence, it could be useful in clinical trials and practice.

MRI-Based Texture Analysis to Differentiate Sinonasal Squamous Cell Carcinoma from Inverted Papilloma.

BACKGROUND AND PURPOSE: Because sinonasal inverted papilloma can harbor squamous cell carcinoma, differentiating these tumors is relevant. The objectives of this study were to determine whether MR imaging-based texture analysis can accurately classify cases of noncoexistent squamous cell carcinoma and inverted papilloma and to compare this classification performance with neuroradiologists' review. MATERIALS AND METHODS: Adult patients who had inverted papilloma or squamous cell carcinoma resected were eligible (coexistent inverted papilloma and squamous cell carcinoma were excluded). Inclusion required tumor size of >1.5 cm and preoperative MR imaging with axial T1, axial T2, and axial T1 postcontrast sequences. Five well-established texture analysis algorithms were applied to an ROI from the largest tumor cross-section. For a training dataset, machine-learning algorithms were used to identify the most accurate model, and performance was also evaluated in a validation dataset. On the basis of 3 separate blinded reviews of the ROI, isolated tumor, and entire images, 2 neuroradiologists predicted tumor type in consensus. RESULTS: The inverted papilloma (n = 24) and squamous cell carcinoma (n = 22) cohorts were matched for age and sex, while squamous cell carcinoma tumor volume was larger (P = .001). The best classification model achieved similar accuracies for training (17 squamous cell carcinomas, 16 inverted papillomas) and validation (7 squamous cell carcinomas, 6 inverted papillomas) datasets of 90.9% and 84.6%, respectively (P = .537). For the combined training and validation cohorts, the machine-learning accuracy (89.1%) was better than that of the neuroradiologists' ROI review (56.5%, P = .0004) but not significantly different from the neuroradiologists' review of the tumors (73.9%, P = .060) or entire images (87.0%, P = .748). CONCLUSIONS: MR imaging-based texture analysis has the potential to differentiate squamous cell carcinoma from inverted papilloma and may, in the future, provide incremental information to the neuroradiologist.

Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension.

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

MRI texture analysis predicts p53 status in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Head and neck cancer is common, and understanding the prognosis is an important part of patient management. In addition to the Tumor, Node, Metastasis staging system, tumor biomarkers are becoming more useful in understanding prognosis and directing treatment. We assessed whether MR imaging texture analysis would correctly classify oropharyngeal squamous cell carcinoma according to p53 status. MATERIALS AND METHODS: A cohort of 16 patients with oropharyngeal squamous cell carcinoma was prospectively evaluated by using standard clinical, histopathologic, and imaging techniques. Tumors were stained for p53 and scored by an anatomic pathologist. Regions of interest on MR imaging were selected by a neuroradiologist and then analyzed by using our 2D fast time-frequency transform tool. The quantified textures were assessed by using the subset-size forward-selection algorithm in the Waikato Environment for Knowledge Analysis. Features found to be significant were used to create a statistical model to predict p53 status. The model was tested by using a Bayesian network classifier with 10-fold stratified cross-validation. RESULTS: Feature selection identified 7 significant texture variables that were used in a predictive model. The resulting model predicted p53 status with 81.3% accuracy (P < .05). Cross-validation showed a moderate level of agreement (κ = 0.625). CONCLUSIONS: This study shows that MR imaging texture analysis correctly predicts p53 status in oropharyngeal squamous cell carcinoma with ∼80% accuracy. As our knowledge of and dependence on tumor biomarkers expand, MR imaging texture analysis warrants further study in oropharyngeal squamous cell carcinoma and other head and neck tumors.

Exposure of two Eutrema salsugineum (Thellungiella salsuginea) accessions to water deficits reveals different coping strategies in response to drought.

Eutrema salsugineum is an extremophile related to Arabidopsis. Accessions from Yukon, Canada and Shandong, China, were evaluated for their tolerance to water deficits. Plants were exposed to two periods of water deficit separated by an interval of re-watering and recovery. All plants took the same time to wilt during the first drought exposure but Yukon plants took 1 day longer than Shandong plants following the second drought treatment. Following re-watering and turgor recovery, solute potentials of Shandong leaves returned to predrought values while those of Yukon leaves were lower than predrought levels consistent with having undergone osmotic adjustment. Polar metabolites profiled in re-watered plants showed that different metabolites are accumulated by Yukon and Shandong plants recovering from a water deficit with glucose more abundant in Yukon and fructose in Shandong leaves. The drought-responsive expression of dehydrin genes RAB18, ERD1, RD29A and RD22 showed greater changes in transcript abundance in Yukon relative to Shandong leaves during both water deficits and recovery with the greatest difference in expression appearing during the second drought. We propose that the initial exposure of Yukon plants to drought renders them more resilient to water loss during a subsequent water deficit leading to delayed wilting. Yukon plants also established a high leaf water content and increased specific leaf area during the second deficit. Shandong plants undergoing the same treatment regime do not show the same beneficial drought tolerance responses and likely use drought avoidance to cope with water deficits.

Corpus callosum volume and interhemispheric transfer in multiple sclerosis.

BACKGROUND: The corpus callosum (CC) is frequently compromised in patients with multiple sclerosis (MS). Structural and functional measurements of the CC may be useful to monitor the progression of the disease. The aim of this pilot study was to determine if bimanual tactile temporal thresholds correlates with CC volume. A tactile temporal threshold is the longest temporal interval that separates the onsets of two tactile stimuli when they are judged by the observer as simultaneous. Judgments to bimanual stimulations require interhemispheric transfer via the CC. METHODS: Thresholds were examined in MS patients and matched controls. Magnetic resonance (MR) images were acquired on a 3T MR system within 48 hours of clinical assessment and measurement of thresholds. RESULTS: Corpus callosum volume was assessed by using a semiautomatic livewire algorithm. The CC volume was smaller (by 21% on average, p < 0.01) and thresholds were higher (by 49% on average, p < 0.03) in MS patients when compared to controls. A significant correlation (r = -0.66, p = 0.01) between CC volume and thresholds emerged for the MS patients. CONCLUSION: Measuring treatment benefits of neuroprotective and repair therapies is a well recognized challenge in MS research. The overall findings of this study suggest that these measurements, which involve the transfer of information interhemispherically via the CC, may be promising outcome measures that warrant further scientific exploration to develop a model to measure recovery.

3T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing-remitting multiple sclerosis: a 3-year pilot study.

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients.

Identification of phosphomethylethanolamine N-methyltransferase from Arabidopsis and its role in choline and phospholipid metabolism.

Three sequential methylations of phosphoethanolamine (PEA) are required for the synthesis of phosphocholine (PCho) in plants. A cDNA encoding an N-methyltransferase that catalyzes the last two methylation steps was cloned from Arabidopsis by heterologous complementation of a Saccharomyces cerevisiae cho2, opi3 mutant. The cDNA encodes phosphomethylethanolamine N-methyltransferase (PMEAMT), a polypeptide of 475 amino acids that is organized as two tandem methyltransferase domains. PMEAMT shows 87% amino acid identity to a related enzyme, phosphoethanolamine N-methyltransferase, an enzyme in plants that catalyzes all three methylations of PEA to PCho. PMEAMT cannot use PEA as a substrate, but assays using phosphomethylethanolamine as a substrate result in both phosphodimethylethanolamine and PCho as products. PMEAMT is inhibited by the reaction products PCho and S-adenosyl-l-homocysteine, a property reported for phosphoethanolamine N-methyltransferase from various plants. An Arabidopsis mutant with a T-DNA insertion associated with locus At1g48600 showed no transcripts encoding PMEAMT. Shotgun lipidomic analyses of leaves of atpmeamt and wild-type plants generated phospholipid profiles showing the content of phosphatidylmethylethanolamine to be altered relative to wild type with the content of a 34:3 lipid molecular species 2-fold higher in mutant plants. In S. cerevisiae, an increase in PtdMEA in membranes is associated with reduced viability. This raises a question regarding the role of PMEAMT in plants and whether it serves to prevent the accumulation of PtdMEA to potentially deleterious levels.

T2 MRI texture analysis is a sensitive measure of tissue injury and recovery resulting from acute inflammatory lesions in multiple sclerosis.

T2 hyperintensity is pathologically non-specific in multiple sclerosis (MS) yet lesion analysis remains an important disease outcome. Texture analysis based on the polar Stockwell Transform (PST) was performed on twelve acute T2 lesions before, during, and after the development of gadolinium-enhancement. When regular myelin structure is disrupted coarse texture increases because tissue becomes disorganized. Coarse texture was quantified as the sum of low frequency energy (sumLFE). Matching regions of contralateral and general normal appearing white matter (NAWM) and chronic T2 lesions were analyzed in parallel as controls. Coarse texture increased in acute lesions during enhancement (p<0.05) then variably recovered. It remained stable in NAWM and tended to increase in chronic T2 lesions. Seven of twelve acute lesions persisted visually at 8 months and the sumLFE was higher in these visually persistent lesions (p<0.05) than in resolved lesions. The sumLFE at month 8 correlated with that in pre-lesional NAWM and in acute lesions (p<0.05) and was independent of lesion volume, signal intensity (SI), and location. This study suggests that PST texture analysis extracts more information about tissue integrity than conventional MRI analysis that relies on lesion size and SI. Texture analysis also appears to identify abnormalities in pre-lesional NAWM, to measure tissue injury in acute lesions, predict poor recovery, and detect mild ongoing tissue injury in chronic T2 lesions. PST texture analysis using conventional MRI may therefore provide valuable new insights into lesion pathology by measuring tissue integrity. This small longitudinal study supports further validation of the PST technique.

Impact of particle size distribution on rheological and textural properties of chocolate models with reduced fat content.

With an increasing consumption of lipids nowadays, decreasing the fat content in food products has become a trend. Chocolate is a fat-based suspension that contains about 30%wt fat. Reducing fat content causes an increase in the molten chocolate viscosity. This leads to 2 major issues: difficulties in the process and a loss of eating quality in the final product, reported to have poor in-mouth melting properties, remain hard, and difficult to swallow. Literature shows that optimizing the particle size distribution (PSD), that is, having one with an increased packing fraction, can decrease the viscosity of highly concentrated suspensions. This study focuses on the impact of the PSD and fat content on the rheological properties, melting behavior, and hardness of chocolate models (dispersions of sugar in fat). We show that optimizing the PSD while reducing the fat content to a critical amount (22%wt) can decrease the viscosity of the molten material and reduce the hardness of the crystallized chocolate models. Melting in the mouth, characterized by an in vitro collapse speed, is faster for the samples with an optimized PSD. The decrease in the viscosity by optimizing the PSD in systems with a constant fraction of medium phase is based on the decrease of interparticle contact, reducing the particle aggregates strength, and structure buildup during flow or meltdown. In its crystallized state, the particle network is less interconnected, providing less resistance to breakage and meltdown.

Deep grey matter "black T2" on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis.

T2 hypointensity (black T2, BT2) in the deep grey matter of multiple sclerosis (MS) patients correlate weakly with disability at 1.5 T. BT2 is likely to be caused by abnormal iron deposition. We compared the correlation between disability and deep grey matter BT2 measured on 3 T MRI and on 1.5 T MRI in 17 MS patients. We observed a significant correlation between expanded disability status scale and signal intensity on 3 T MRI in the globus pallidus and the caudate nucleus (r = -0.5, P < 0.05). BT2 at 3 T may be a useful MRI measure associated with disability in MS and warrants further study.

The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study.

Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.

Resolution-dependent estimates of multiple sclerosis lesion loads.

BACKGROUND: Changes in brain lesion loads assessed with magnetic resonance imaging obtained at 1.5 Telsa (T) are used as a measure of disease evolution in natural history studies and treatment trials of multiple sclerosis. METHODS: A comparison was made between the total lesion volume and individual lesions observed on 1.5 T images and on high-resolution 4 T images. Lesions were quantified using a computer-assisted segmentation tool. RESULTS: There was a 46% increase in the total number of lesions detected with 4 T versus 1.5 T imaging (p < 0.005). The 4 T also showed a 60% increase in total lesion volume when compared with the 1.5 T (p < 0.005). In several instances, the 1.5 T scans showed individual lesions that coalesced into larger areas of abnormality in the 4 T scans. The relationship between individual lesion volumes was linear (slope 1.231) showing that the lesion volume observed at 4 T increased with the size of the lesion detected at 1.5 T. The 4 T voxels were less than one quarter the size of those used at 1.5 T and there were no consistent differences between their signal-to-noise ratios. CONCLUSIONS: The increase in signal strength that accompanied the increase in field strength compensated for the loss in signal amplitude produced by the use of smaller voxels. This enabled the acquisition of images with improved resolution, resulting in increased lesion detection at 4 T and larger lesion volumes.