Effects of aquatic exercise on appetitive responses in adolescents with obesity: An exploratory study.

Aquatic exercise has been suggested as a beneficial modality to improve weight loss, cardiorespiratory fitness and quality of life in adolescents with obesity; however, its impact on appetite control in youth remains unknown. The aim of this preliminary study was to examine the effect of an acute aquatic exercise session on energy intake (EI), appetite feelings and food reward in adolescents with obesity. Twelve adolescents with obesity (12-16 years, Tanner stage 3-5, 9 males) randomly completed two conditions: i) control (CON); ii) aquatic exercise session (AQUA). One hour before lunch, the adolescents stayed at rest outside the water in a quiet room for 45 min on CON while they performed a 45-min aquatic exercise session on AQUA. Ad libitum EI and macronutrients were assessed at lunch and dinner, subjective appetite feelings taken at regular intervals, and food reward measured before and after lunch. Paired T-test showed that EI was not different between CON and AQUA at lunch (1333 ± 484 kcal vs 1409 ± 593 kcal; p = 0.162) and dinner (528 ± 218 kcal vs 513 ± 204 kcal; p = 0.206). Total daily ad libitum EI was significantly higher on AQUA (1922 ± 649 kcal) compared with CON (1861 ± 685 kcal; p = 0.044) but accounting for the exercise-induced energy expenditure, relative energy intake did not differ (2263 ± 732 kcal vs 2117 ± 744 kcal, p = 0.304). None of the appetite feelings (hunger, fullness, prospective food consumption and desire to eat) and food reward dimensions were significantly different between conditions. These preliminary and exploratory results suggest that an acute aquatic-exercise session might not induce energy compensatory responses in adolescents with obesity.

Satiety responsiveness but not food reward is modified in response to an acute bout of low versus high intensity exercise in healthy adults.

To compare the effect of iso-caloric low and high intensity exercises on Satiety Quotient and Food Reward in response to a fixed meal in healthy young adults. Anthropometric measurements, body composition (BIA), aerobic capacity (VO2 max) and food preferences were assessed in 19 healthy normal-weight young adults (21 ±â€¯0.5 years old, 10 men). They randomly completed 3 experimental sessions: i) control session without exercise (CON); ii) High Intensity exercise session (HIE); iii) Low intensity exercise session (LIE). Thirty minutes after exercise or rest, then received a fixed lunch. Food reward (Leeds Food Preference Questionnaire) was assessed before and after the meal. Appetite sensations were assessed at regular intervals, SQ was calculated from the lunch meal and self-reported food intake was collected for the rest of the day. Mean body weight was 66.7 ±â€¯9.2 kg, body mass index was 22.3 ±â€¯2.9 kg/m2 and FM% was 18.7 ±â€¯6.8%. Appetite feelings did not differ between conditions and were not affected by exercise. SQ for satiety was not different between conditions. SQ hunger on CON was significantly higher than on LIE and HIE (p ≤ 0.05) with no difference between exercise conditions. SQ for desire to eat was significantly higher on CON versus HIE (p ≤ 0.01) with no differences between CON and LIE and between exercise sessions. SQ PFC was significantly lower on HIE compared with CON (p = 0.02) with no differences between LIE and CON and between LIE and HIE. Food reward was not significantly different between the three condition as well as self-reported total food and macronutrient intake for the rest of the days. Acute exercise, depending on its intensity, might affect the satiating response to food intake in healthy adults, without altering food reward.

Global transcriptome profiling of mild relapsing-remitting versus primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Genetic research in multiple sclerosis (MS) mostly compares patients with MS with healthy controls, but does not differentiate between MS disease courses. We compared peripheral blood gene expression patterns between extremes of MS phenotypes, i.e. patients with mild relapsing-remitting MS (mRRMS) and primary progressive MS (PPMS). METHODS: We analyzed global gene expression profiles of peripheral blood samples of age- and gender-matched patients with mRRMS and PPMS. Detailed bioinformatic and gene set enrichment analysis, pathway and principle component analyses were used to identify differentially expressed genes and pathways. RESULTS: A total of 84 genes were significantly deregulated between the groups. Of those, 19 had been previously reported to be deregulated in patients with MS as compared with healthy controls, including major histocompatibility complex, interferon receptor 2 and interleukin 6 receptor. Detailed molecular pathway analysis revealed significant up-regulation of antigen processing and presentation, leukocyte transendothelial migration, nucleotide-binding oligomerization domain-like receptor signaling, chemokine signaling and down-regulation of RNA transport, spliceosome and aminoacyl-tRNA biosynthesis pathways in PPMS compared with mRRMS. CONCLUSION: Our analyses show significant differences between mRRMS and PPMS gene expression. Surprisingly, the differentially expressed genes were mostly involved in immunological and inflammatory pathways, suggesting that the difference in MS phenotypes is caused primarily by a difference in immune responses. It should be kept in mind that our analyses were in peripheral blood only, and that the observed differences in inflammatory pathways may be a substrate of the analysed tissue. Further research into gene expression differences between disease courses including analyses in central nervous system tissue is warranted.

Smoking does not influence disability accumulation in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The modifiable risk factor cigarette smoking has been associated with an increased risk of developing multiple sclerosis (MS) and with disease activity in relapsing-remitting MS. However, less is known about the effect of smoking on disease progression in progressive MS. Here the association between cigarette smoking and disability accumulation in primary progressive MS (PPMS) is investigated. METHODS: Kaplan-Meier survival analyses and Cox proportional hazard modelling were used to investigate the influence of cigarette smoking on the risk of reaching Expanded Disability Status Scale (EDSS) 4 and 6 as well as the time from EDSS 4 to 6 in patients with PPMS. RESULTS: In all, 416 patients with PPMS and available smoking history were identified. Median time to EDSS 4 was 4 years in ever-smokers and 5 years in never-smokers (P = 0.27), and it was 9 years to EDSS 6 in both ever-smokers and never-smokers (P = 0.48). Smokers were not at increased risk of faster progression to EDSS 4, 6 and from EDSS 4 to 6. Age at disease onset was the strongest risk factor for progression to EDSS 4, 6 and from EDSS 4 to 6. CONCLUSIONS: Our investigation of a large and well-characterized population based PPMS cohort suggests that cigarette smoking does not influence disability accumulation in PPMS. Our findings support the idea that PPMS is driven by different underlying pathomechanisms than relapsing-remitting MS.

Application and a proposed modification of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Canadian cohort of patients with clinically isolated syndromes.

BACKGROUND: The 2005 and 2010 McDonald criteria utilize magnetic resonance imaging (MRI) to provide evidence of disease dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis (MS) in patients who have clinically isolated syndromes (CIS). METHODS: Data from 109 CIS patients not satisfying the 2005 criteria at entry into a randomized controlled minocycline trial were analyzed to determine the proportion who would have been diagnosed with MS at screening based on 2010 criteria. The impact of including symptomatic, as well as asymptomatic, MRI lesions to confirm DIT was also explored. RESULTS: Thirty percent (33/109) of patients, retrospectively, met the 2010 criteria for a diagnosis of MS at baseline. When both symptomatic and asymptomatic lesions were used to confirm DIT, three additional patients met the 2010 criteria. There was a significant 10.1% increase in the proportion of patients who met the 2010 DIS criteria, compared with the 2005 DIS criteria; however, two patients satisfied the 2005 DIS but not 2010 DIS criteria. CONCLUSION: Using 2010 McDonald criteria, 30% of the CIS patients could be diagnosed with MS using a single MRI scan. Inclusion of symptomatic lesions in the DIT criteria further increases this proportion to 33%.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Using machine learning to predict perfusionists' critical decision-making during cardiac surgery.

The cardiac surgery operating room is a high-risk and complex environment in which multiple experts work as a team to provide safe and excellent care to patients. During the cardiopulmonary bypass phase of cardiac surgery, critical decisions need to be made and the perfusionists play a crucial role in assessing available information and taking a certain course of action. In this paper, we report the findings of a simulation-based study using machine learning to build predictive models of perfusionists' decision-making during critical situations in the operating room (OR). Performing 30-fold cross-validation across 30 random seeds, our machine learning approach was able to achieve an accuracy of 78.2% (95% confidence interval: 77.8% to 78.6%) in predicting perfusionists' actions, having access to only 148 simulations. The findings from this study may inform future development of computerised clinical decision support tools to be embedded into the OR, improving patient safety and surgical outcomes.

Diet- but not exercise-induced iso-energetic deficit induces compensatory appetitive responses.

Although physical exercise and dietary restriction can be both used to induce energy deficits, they have been suggested to favor different compensatory appetitive responses. While dietary restriction might favor increased subsequent energy intake and appetite sensations, such compensatory responses have not been observed after a similar deficit by exercise. The present work provides a first overview of the actual evidences discussing the effects of iso-energetic deficits induced by exercise versus dietary restriction on subsequent energy intake, appetite sensations, and on the potentially involved hedonic and physiological mechanisms.

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients.

AIMS/HYPOTHESIS: Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. METHODS: Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were measured in muscle tissue. Lipid accumulation in muscle and primary myotubes was estimated by Oil Red O staining and fatty acid translocase (FAT)/CD36 localisation by immunofluorescence. RESULTS: Obesity and type 2 diabetes are independently characterised by skeletal muscle IMCL accumulation and permanent FAT/CD36 relocation. Mitochondrial function is not reduced in type 2 diabetes. IMCL accumulation was independent of type 2 diabetes in cultured myotubes and was correlated with obesity markers of the donor. In obese participants, membrane relocation of FAT/CD36 is a determinant of IMCL accumulation. CONCLUSIONS/INTERPRETATION: In skeletal muscle, mitochondrial function is normal in type 2 diabetes, while IMCL accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

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.

Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial.

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing-remitting multiple sclerosis.

High dose oral steroids commonly used to treat relapses in Canadian MS clinics.

BACKGROUND: Glucocorticoid treatment improves the speed of functional recovery of acute multiple sclerosis (MS) relapses but has not been shown to provide any long-term functional benefit. There is currently no convincing evidence that the clinical benefit is influenced by the route of administration or the dosage of glucocorticoid, or the particular glucocorticoid prescribed. Recent studies support similarities in the bioequivalence and in the clinical effect of high dose oral corticosteroids for MS relapses. OBJECTIVE: This survey aimed to determine the relapse treatment preferences of clinicians in Canadian MS clinics. METHODS: Members of the Canadian Network of MS Clinics are linked by an email server. A one page survey was distributed to the group to determine and report use of corticosteroids to manage MS relapses amongst Canadian MS specialists. RESULTS: Fifty-one clinicians from 17 MS clinics were surveyed. 32 (63%) surveys were returned representing 16 clinics. Five doses are most commonly prescribed, usually without a taper. Three or four doses and the use of a corticosteroid taper, however, are not uncommon. Gastric cytoprotection and sedatives are often prescribed for use as needed. CONCLUSION: This survey illustrates that when Canadian clinicians with expertise in managing MS treat MS relapses they choose high dose corticosteroids, either oral or i.v. The results therefore represent Canadian practice as these clinicians provide direct patient care and influence care by community neurologists. Until evidence clearly identifies a superior practice all options should be available to clinicians and their patients.

FLAIR2 improves LesionTOADS automatic segmentation of multiple sclerosis lesions in non-homogenized, multi-center, 2D clinical magnetic resonance images.

BACKGROUND: Accurate segmentation of MS lesions on MRI is difficult and, if performed manually, time consuming. Automatic segmentations rely strongly on the image contrast and signal-to-noise ratio. Literature examining segmentation tool performances in real-world multi-site data acquisition settings is scarce. OBJECTIVE: FLAIR2, a combination of T2-weighted and fluid attenuated inversion recovery (FLAIR) images, improves tissue contrast while suppressing CSF. We compared the use of FLAIR and FLAIR2 in LesionTOADS, OASIS and the lesion segmentation toolbox (LST) when applied to non-homogenized, multi-center 2D-imaging data. METHODS: Lesions were segmented on 47 MS patient data sets obtained from 34 sites using LesionTOADS, OASIS and LST, and compared to a semi-automatically generated reference. The performance of FLAIR and FLAIR2 was assessed using the relative lesion volume difference (LVD), Dice coefficient (DSC), sensitivity (SEN) and symmetric surface distance (SSD). Performance improvements related to lesion volumes (LVs) were evaluated for all tools. For comparison, LesionTOADS was also used to segment lesions from 3 T single-center MR data of 40 clinically isolated syndrome (CIS) patients. RESULTS: Compared to FLAIR, the use of FLAIR2 in LesionTOADS led to improvements of 31.6% (LVD), 14.0% (DSC), 25.1% (SEN), and 47.0% (SSD) in the multi-center study. DSC and SSD significantly improved for larger LVs, while LVD and SEN were enhanced independent of LV. OASIS showed little difference between FLAIR and FLAIR2, likely due to its inherent use of T2w and FLAIR. LST replicated the benefits of FLAIR2 only in part, indicating that further optimization, particularly at low LVs is needed. In the CIS study, LesionTOADS did not benefit from the use of FLAIR2 as the segmentation performance for both FLAIR and FLAIR2 was heterogeneous. CONCLUSIONS: In this real-world, multi-center experiment, FLAIR2 outperformed FLAIR in its ability to segment MS lesions with LesionTOADS. The computation of FLAIR2 enhanced lesion detection, at minimally increased computational time or cost, even retrospectively. Further work is needed to determine how LesionTOADS and other tools, such as LST, can optimally benefit from the improved FLAIR2 contrast.

Training-induced improvement in lipid oxidation in type 2 diabetes mellitus is related to alterations in muscle mitochondrial activity. Effect of endurance training in type 2 diabetes.

AIM: We investigated whether or not, in type 2 diabetic (T2D) patients, an individualized training effect on whole-body lipid oxidation would be associated with changes in muscle oxidative capacity. METHODS: Eleven T2D patients participated in the study. Whole-body lipid oxidation during exercise was assessed by indirect calorimetry during graded exercise. Blood samples for measuring blood glucose and free fatty acids during exercise, and muscle oxidative capacity measured from skeletal muscle biopsy (mitochondrial respiration and citrate synthase activity), were investigated in the patients before and after a 10-week individualized training program targeted at LIPOXmax, corresponding to the power at which the highest rate of lipids is oxidized (lipid oxidation at LIPOXmax). RESULTS: Training induced both a shift to a higher-power intensity of LIPOXmax (+9.1+/-4.2W; P<0.05) and an improvement of lipid oxidation at LIPOXmax (+51.27+/-17.93 mg min(-1); P<0.05). The improvement in lipid oxidation was correlated with training-induced improvement in mitochondrial respiration (r=0.78; P<0.01) and citrate synthase activity (r=0.63; P<0.05). CONCLUSION: This study shows that a moderate training protocol targeted at the LIPOXmax in T2D patients improves their ability to oxidize lipids during exercise, and that this improvement is associated with enhanced muscle oxidative capacity.

Reliability of visual temporal thresholds.

BACKGROUND: Visual processing deficits involving temporal characteristics are typically not captured by the widely used outcome measures (i.e., Expanded Disability Status Scale, Multiple Sclerosis Functional Composite) in multiple sclerosis (MS). Visual temporal thresholds (i.e., measurements of the temporal aspects in visual processing) are typically significantly higher (i.e., prolonged) in MS patients when compared to controls. The test-retest reliability of these thresholds was examined in patients with MS. METHODS: Visual temporal thresholds were measured in 21 stable MS patients during two separate test sessions. Test-retest reliability and the standard error of measurement were calculated. The threshold of change in visual temporal thresholds in MS patients that would correspond to real change beyond measurement error with 95% certainty was also calculated. For comparisons, a control group (n = 10) was included. RESULTS: The test-retest reliability of this measure of visual temporal thresholds was 0.97. The threshold indicating change beyond chance or measurement error with 95% certainty was 11 ms. Higher thresholds were significantly correlated with longer durations of disease. CONCLUSIONS: This measure of visual temporal thresholds has excellent test-retest reliability and a change of greater than 11 ms is highly likely to represent real change in MS patients. The findings indicate that these measurements may provide useful clinical information about functional changes regarding the temporal aspects of the visual system, which is currently not captured by the Extended Disability Status Scale.

Goalpha regulates volatile anesthetic action in Caenorhabditis elegans.

To identify genes controlling volatile anesthetic (VA) action, we have screened through existing Caenorhabditis elegans mutants and found that strains with a reduction in Go signaling are VA resistant. Loss-of-function mutants of the gene goa-1, which codes for the alpha-subunit of Go, have EC(50)s for the VA isoflurane of 1.7- to 2.4-fold that of wild type. Strains overexpressing egl-10, which codes for an RGS protein negatively regulating goa-1, are also isoflurane resistant. However, sensitivity to halothane, a structurally distinct VA, is differentially affected by Go pathway mutants. The RGS overexpressing strains, a goa-1 missense mutant found to carry a novel mutation near the GTP-binding domain, and eat-16(rf) mutants, which suppress goa-1(gf) mutations, are all halothane resistant; goa-1(null) mutants have wild-type sensitivities. Double mutant strains carrying mutations in both goa-1 and unc-64, which codes for a neuronal syntaxin previously found to regulate VA sensitivity, show that the syntaxin mutant phenotypes depend in part on goa-1 expression. Pharmacological assays using the cholinesterase inhibitor aldicarb suggest that VAs and GOA-1 similarly downregulate cholinergic neurotransmitter release in C. elegans. Thus, the mechanism of action of VAs in C. elegans is regulated by Goalpha, and presynaptic Goalpha-effectors are candidate VA molecular targets.

Long-term effects of extreme situational stress on sleep and dreaming.

Sleep data were obtained on 11 patients who had survived traumatic events and who complained of sleep disturbances. Each was awakened from REM and non-REM sleep for dream recall. The patients had lower sleep efficiency indices (because of prolonged sleep latency and larger amounts of "awake" plus "movement" time within sleep periods), shorter REM time, and longer REM latencies than did control subjects. Four of the 11 patients had REM- and non-REM-related nightmares, which, in two sea disaster patients, were associated with REM-related motor activity. The rest of the patients had unusually low dream recall in spite of high eye movement density.

Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis.

BACKGROUND: Prednisone and methylprednisolone are well absorbed orally and have lower treatment costs than IV methylprednisolone, but concern that low-dose corticosteroid may cause increased disease activity and that high oral doses may cause gastric ulceration inhibits use of oral therapy for MS attacks. METHODS: Gastric mucosal injury, detected by measurement of gastric permeability, was examined after five alternate day doses of IV methylprednisolone (1 g) or oral prednisone (1,250 mg) in 21 patients with MS. A triple sugar test solution was consumed at bedtime, and urine was collected overnight. Urine sugar concentrations were determined by high-pressure liquid chromatography. Gastric permeability was expressed as total mg of sucrose excreted. RESULTS: Seventeen patients completed the protocol (12 oral, 5 IV). Baseline sucrose excretion was normal in all. Both groups demonstrated an increase in gastric permeability after steroid treatment, but there was no difference between the two groups (95% CI 95 to 91 mg, p = 0.96). After treatment, three (25%) patients in the oral group, and two (40%) patients the IV group, had modestly abnormal gastric permeability (95% CI 34 to 64%, P = 0.6). CONCLUSIONS: Short-term high-dose oral prednisone is not associated with greater gastric damage, as measured with permeability tests, than IV methylprednisolone. High-dose oral prednisone should be considered a first-line treatment option for MS attacks.

The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis.

OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.

Is delta-aminolevulinic acid dehydratase rate limiting in heme biosynthesis following exposure of cells to delta-aminolevulinic acid?

Understanding the regulation and control of heme/porphyrin biosynthesis is critical for the optimization of the delta-aminolevulinic-acid (ALA)-mediated photodynamic therapy of cancer, in which endogenously produced protoporphyrin IX (PPIX) is the photosensitizer. The human breast cancer cell line MCF-7, the rat mammary adenocarcinoma cell line R3230AC, the mouse mammary tumor cell line EMT-6 and the human mesothelioma cell line H-MESO-1 were used to study ALA-induced PPIX levels and their relationship to delta-aminolevulinic acid dehydratase (ALA-D) activity in vitro. Incubation of these cell lines with 0.5 mM ALA for 3 h resulted in a significant increase in PPIX accumulation, compared with control cells, but there was no significant change in ALA-D activity. Exposure of cells incubated with ALA to 30 mJ/cm2 of fluorescent light, a dose that would cause a 50% reduction in cell proliferation, did not significantly alter the activity of ALA-D. Increasing the activity of porphobilinogen deaminase (PBGD), the enzyme immediately subsequent to ALA-D, by four- to seven-fold via transfection of cells with PBGD complementary DNA did not alter the activity of ALA-D. However, incubation of cells with various concentrations of succinyl acetone, a potent inhibitor of ALA-D, caused a concomitant decline in both PPIX accumulation and ALA-D activity. These data imply that when cells are exposed to exogenous ALA, ALA-D is an important early-control step in heme/porphyrin biosynthesis and that regulation of PPIX synthesis by this dehydratase may impact the effectiveness of ALA-mediated photosensitization.