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The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility. [ABSTRACT FROM AUTHOR]

We describe the novel transcatheter approach, with off-label application of LAA closure device, coiling, and concurrent left anterior descending stenting in the setting of left ventricular (LV) pseudoaneurysm. This case underlines collaboration among interventional cardiology, cardiothoracic, and neurosurgery teams in a challenging, nonsurgical candidate with high risk of LV pseudoaneurysm rupture, and death. ( Level of Difficulty: Advanced. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Transcranial magnetic stimulation (TMS) treatments have shown promise in improving arm recovery in stroke patients. Currently, little is known about patients' experiences with repetitive TMS treatment, and this lack of knowledge may affect optimal implementation in clinical practice. The aim of this explorative study was to gain insight in the perceived effects and experiences of the design and delivery of a rTMS treatment for upper limb recovery from the perspectives of stroke patients., Methods: This qualitative study was conducted as part of a randomized controlled trial (RCT) in a specialized rehabilitation center. Data were collected through face-to-face semi-structured interviews with 13 stroke patients who completed a 10-day rTMS intervention for upper limb recovery. The interviews were recorded, transcribed verbatim and analyzed using thematic analysis., Results: The major themes that emerged from the patients' feedback were the following: positive experiences of the treatment (experienced physical effects, comfort, therapeutic relationship, receiving information, learning about the brain, no burden of added rTMS treatment session, no unpleasant aspects), concerns (effects of stimulation of the brain, equipment, logistics), general experience of recovery, experienced psychological effects (grateful, sense of purpose, recovery as extra motivation to exercise, disappointment and hope of group allocation), and motivation to participate (personal benefit and cognitions, altruism). Important components related to the positive experience of the design and delivery of the treatment included comfort (i.e. moment of relaxation) and the sensation of a painless treatment without side-effects. Key concerns included uncertainty and anxiety about possible negative consequences and group allocation., Conclusions: This study demonstrates that rTMS is well accepted by stroke patients with an upper limb paresis. Besides the expectation of a therapeutic benefit, the patients reported various psychological effects. Positive experiences, such as the provision of a short moment of relaxation each day, could have practical implications for clinical stroke rehabilitation settings aimed at improving patient satisfaction. Explanation about and feedback from routine motor recovery progression monitoring at fixed times post-stroke is also valued by patients. Negative emotions may be limited or avoided by transparent and recurrent information delivery in future trials.

The neonatal, infant, child, and maternal mortality rates in Haiti are the highest in the Western Hemisphere, with rates similar to those found in Afghanistan and several African countries. We identify several factors that have perpetuated this health care crisis and summarize the literature highlighting the most cost-effective, evidence-based interventions proved to decrease these mortality rates in low- and middle-income countries.To create a major change in Haiti's health care infrastructure, we are implementing two strategies that are unique for low-income countries: development of a countrywide network of geographic "community care grids" to facilitate implementation of frontline interventions, and the construction of a centrally located referral and teaching hospital to provide specialty care for communities throughout the country. This hospital strategy will leverage the proximity of Haiti to North America by mobilizing large numbers of North American medical volunteers to provide one-on-one mentoring for the Haitian medical staff. The first phase of this strategy will address the child and maternal health crisis.We have begun implementation of these evidence-based strategies that we believe will fast-track improvement in the child and maternal mortality rates throughout the country. We anticipate that, as we partner with private and public groups already working in Haiti, one day Haiti's health care system will be among the leaders in that region.

Aims: Parametric imaging of myocardial perfusion provides useful visual information for the diagnosis of coronary artery disease (CAD). We developed a technique for automated detection of perfusion defects based on quantitative analysis of parametric perfusion images and validated it against coronary angiography., Methods and Results: Contrast-enhanced, apical 2-, 3- and 4-chamber images were obtained at rest and with dipyridamole in 34 patients with suspected CAD. Images were analyzed to generate parametric perfusion images of the standard contrast-replenishment model parameters A, beta and A.beta. Each parametric image was divided into six segments, and mean parameter value (MPV) was calculated for each segment. Segmental MPV ratio between stress and rest was defined as a flow reserve index (FRI). Receiver operating characteristics (ROC) analysis was used in a Study group (N=17) to optimize FRI threshold and the minimal number of abnormal segments per vascular territory (LAD and non-LAD), required for automated detection of stress-induced perfusion defects. The optimized detection algorithm was then tested prospectively in the remaining 17 patients (Test group). LAD and non-LAD stenosis >70% was found in 19 and 17 patients, respectively. In the Study group, FRI threshold was: LAD=0.95 and non-LAD=0.68, minimal number of abnormal segments was four and two, correspondingly. Sensitivity, specificity and accuracy in the Test group were: 75%, 67% and 71% in the LAD, and 75%, 75% and 75% in the non-LAD territories., Conclusion: Automated quantitative analysis of contrast echocardiographic parametric perfusion images is feasible and may aid in the objective detection of CAD.

Aims: Determination of left ventricular (LV) volumes and ejection fraction (EF) from two-dimensional echocardiographic (2DE) images is subjective, time-consuming, and relatively inaccurate because of foreshortened views and the use of geometric assumptions. Our aims were (1) to validate a new method for rapid, online measurement of LV volumes from real-time three-dimensional echocardiographic (RT3DE) data using cardiac magnetic resonance (CMR) as the reference and (2) to compare its accuracy and reproducibility with standard 2DE measurements., Methods and Results: CMR, 2DE, and RT3DE datasets were obtained in 50 patients. End-systolic and end-diastolic volumes (ESV and EDV) were calculated from the 2DE images using biplane method of disks. ES and ED RT3DE datasets were analysed using prototype software designed to automatically detect the endocardial surface using a deformable shell model and calculate ESV and EDV from voxel counts. 2DE and RT3DE-derived volumes were compared with CMR (linear regression, Bland-Altman analysis). In most patients, analysis of RT3DE data required <2 min per patient. RT3DE measurements correlated highly with CMR (r: 0.96, 0.97, and 0.93 for EDV, ESV, and EF, respectively) with small biases (-14 mL, -6.5 mL, -1%) and narrow limits of agreement (SD: 17 mL, 16 mL, 6.4%). 2DE measurements correlated less well with CMR (r: 0.89, 0.92, 0.86) with greater biases (-23 mL, -15 mL, 1%) and wider limits of agreement (SD: 29 mL, 24 mL, 9.5%). RT3DE resulted in lower intra-observer (EDV: 7.9 vs. 23%; ESV: 7.6 vs. 26%) and inter-observer variability (EDV: 11 vs. 26%; ESV: 13 vs. 31%)., Conclusion: Semi-automated detection of the LV endocardial surface from RT3DE data is suitable for clinical use because it allows rapid, accurate, and reproducible measurements of LV volumes, superior to conventional 2DE methods.

Objectives: We tested the feasibility of real-time three-dimensional echocardiographic (RT3DE) perfusion imaging and developed and validated an algorithm for volumetric analysis of myocardial contrast inflow. The study included three protocols wherein perfusion was measured: 1) in an ex-vivo model of controlled global coronary flow, 2) in an in-vivo model during regional perfusion variations, and 3) in humans during pharmacologically induced hyperemia., Background: The RT3DE technology offers an opportunity for myocardial perfusion imaging without multi-slice reconstruction and repeated contrast maneuvers., Methods: Electrocardiographically triggered harmonic RT3DE datasets were acquired (Philips 7500) while infusion of Definity was initiated and reached a steady state. Protocol 1 was performed in nine isolated rabbit hearts and included three coronary flow levels. In protocol 2, changes in regional perfusion caused by partial left anterior descending artery occlusion were measured in five pigs. In protocol 3, adenosine-induced changes in perfusion were measured in eight normal volunteers. Myocardial video-intensity (MVI) was measured over time in three-dimensional (3D) slices to calculate peak contrast inflow rate (PCIR). In pigs, PCIR was measured on a regional basis and validated against microspheres., Results: The RT3DE imaging allowed selection of slices for perfusion analysis in rabbit hearts, pigs, and humans. Administration of contrast resulted in clearly visible and quantifiable changes in MVI. In rabbits, The PCIR progressively decreased with coronary flow (p < 0.0001). In pigs, coronary occlusion caused a 59 +/- 26% decrease in PCIR exclusively in the left anterior descending artery territory (p < 0.05) in agreement with microspheres. In humans, adenosine increased PCIR to 198 +/- 57% of baseline (p < 0.05)., Conclusions: Contrast-enhanced RT3DE imaging provides the basis for volumetric imaging and quantification of myocardial perfusion.

Background: We hypothesized that color encoding of endocardial motion could aid less-experienced readers in detection of wall-motion abnormalities at rest and stress in patients with poor acoustic windows., Methods: Color-encoded images (color kinesis) were obtained at rest and peak dobutamine stress in 4 standard views during intravenous infusion of contrast agent in 117 patients with poorly visualized endocardium. In 101 of 117 patients (86%), in whom contrast enhancement allowed endocardial tracking, images were reviewed by two expert readers without color overlays. Each reader graded regional wall motion as normal, abnormal, or uninterpretable, and their consensus grades served as a gold standard. The same images were then reviewed and graded with and without color overlays by 3 cardiology fellows. The accuracy of the interpretation was calculated against the gold standard separately for the 3 vascular territories (left anterior descending, left circumflex, and right coronary arteries) and averaged for the 3 fellows., Results: With the addition of color encoding: (1) the number of uninterpretable segments decreased by 55% at rest and 61% at peak stress; and (2) all 3 fellows reached higher levels of accuracy in all 3 vascular territories both at rest (6%-82% average) and at stress (73%-80%)., Conclusion: The addition of color encoding of wall motion to contrast-enhanced images obtained in patients with poor acoustic windows during stress tests improves the interpretation of regional left ventricular function by less-experienced readers.

Objective: The purpose of this study was to compare the effect of insulin glargine (glargine) and NPH insulin (NPH) on long-term outcomes in type 2 diabetes patients using the Diabetes Mellitus Model (DMM)., Methods: The DMM predicts short- and long-term complications over ten years using data in studies published previously. The main effect on outcome is the influence of the treatment on the HbA1c level which is simulated over time. The simulation was based on a cohort size of 10,000 type 2 diabetes patients taking either glargine or NPH. The best scenario, baseline scenario and worst case scenario were simulated based on differences of 0.13%, 0.44% and 0.85%, respectively, in HbA1c values and corresponding to potentially attainable improvements with comparable or lower hypoglycemia rates in glargine-treated patients and NPH-treated patients. Assumptions for scenarios 1, 2 and 3 were based on a regression analysis of clinical trial data (pooled data clinical trials comparing glargine and NPH) in which the effect of glargine on the HbA1c/hypoglycemia incidence ratio was superior to that of NPH., Results: The relative risks (RR, glargine/NPH) obtained for scenarios 1, 2 and 3 were 0.97, 0.89 and 0.81, respectively, for long-term microvascular complications and 0.99, 0.95 and 0.91, respectively, for long-term macrovascular complications. RR reductions ranged from 1% in the less optimistic scenario to > 20% in the "best case" scenario. Sensitivity analyses showed that variations in the mean baseline HbA1c values and duration of the diabetes were without effect on these outcomes., Conclusions: Although there is a need to corroborate the results of these simulations with real, long-term clinical data, they have demonstrated that, assuming comparable or lower rates of hypoglycemia, a better glycemic control (HbA1c reduction) can be expected with glargine when compared to NPH together with a reduction in long-term complications, mortality and associated costs.

Recognizing left ventricular (LV) systolic dysfunction is critical. The investigators sought to evaluate whether nurses could be trained to use a hand-carried ultrasound (HCU) device to screen for LV systolic dysfunction in high-risk patients. Sixty-three patients from an outpatient diabetes clinic underwent brief echocardiographic examinations by nurses using HCU devices. Of the 63 patients enrolled in the study, 3 (4.7%) had LV systolic dysfunction. The nurses correctly identified these 3 patients as having LV systolic dysfunction (sensitivity 100%, negative predictive value 100%). The identification of occult LV systolic dysfunction in diabetic patients may allow the initiation of therapies known to improve prognosis.

The aim of the investigation was to assess the pharmacokinetic characteristics and safety of articaine HCl used in tumescent local anesthesia for liposuction. Maximum plasma concentrations of articaine HCl were observed from 136 to 264 ng/mL, on average, from 1.2 to 4.3 hours after the start of infiltration, depending on the area of liposuction. The average extent of absorption ranged from 827 to 2203 ng*h/mL. Average maximum plasma concentrations of articainic acid ranged from 1719 to 7292 ng/mL. The high articainic acid concentrations at 1 hour after the start of infiltration indicate that articaine HCl was hydrolyzed rapidly by esterases in tissue and plasma. Although up to 38.2 mg/kg body weight articaine HCl was applied, no cardiac side effects or symptoms of central nervous intoxication occurred. Articaine HCl provided a safe and sufficient analgesia for tumescent liposuction.

We compared the patterns of the pro-inflammatory cytokines, interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory cytokines, interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) from peripheral blood of male and female patients with relapsing-remitting (RR) and secondary progressive (SP) forms of multiple sclerosis (MS). The relationships between pro-inflammatory cytokines and disability (expanded disability status scale, EDSS) were also examined. Peripheral blood anti-coagulated with heparin was obtained from 47 MS patients (30 women and 17 men) and activated with phorbol-12-myristate 13 acetate (PMA) and ionomycin in the presence of brefeldin A and stained for flow cytometry with fluorescently labeled antibodies against intracellular IFN-gamma, TNF-alpha, IL-2, IL-4 and IL-10. The T cells were delineated with peridinin chlorophyll protein (Per-CP) labeled anti-CD3 antibody. The stained samples were analyzed on a flow cytometer to assess the intracellular pro-inflammatory cytokine patterns. The levels of interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) were measured in plasma using enzyme-linked immunoassay. The percentage of TNF-alpha-producing CD3 positive cells was significantly higher (P=0.045) in men (mean+/-S.D., 39+/-13%) than in women (mean+/-S.D., 29+/-13%) RR-MS patients. The percentage of CD3 positive cells producing IFN-gamma was significantly correlated with EDSS in females but not in males (Spearman rank correlation r(S)=0.49, P=0.018). The secretion of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha, is influenced by gender in MS patients and may contribute to the sexual dimorphism of MS.

The objective of this work was to assess the effect of interferon beta-1a (Avonex) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30 microg interferon beta-1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem-cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon beta-1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem-cerebellar syndromes, and spinal cord syndromes.

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon beta-1a (IFNbeta-1a, 30 microg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6-month intervals. The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNbeta-1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between-group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNbeta-1a group. These results support and extend previous observations of significant beneficial effects of IFNbeta-1a for relapsing MS.

The purpose of this study was to determine whether the expression of cytochrome P450 (CYP) enzyme mRNAs, other drug-metabolizing enzyme mRNAs, and transporter mRNAs can be detected using DNA arrays. Total RNA was isolated from peripheral blood mononuclear cells of 10 multiple sclerosis patients and 10 age- and sex-matched controls. The mRNA was reverse transcribed to radiolabeled cDNA, and the resultant cDNA was used to probe a DNA array containing several thousand known human genes. The signals corresponding to several CYPs, drug-metabolizing, and transporter mRNAs was substantially above background. The results demonstrate that the DNA array technique has the sensitivity and the selectivity for applications in the pharmaceutical sciences. The mean values for mRNAs of specific CYPs and drug-metabolizing enzymes in peripheral blood cells were compared with reported values for liver. The capabilities of DNA arrays may prove useful for characterizing CYP expression in a variety of clinical samples.

Background: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS., Objective: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials., Methods: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon beta-1a (IFNbeta-1a)-treated patients with mild to moderate disability relapsing-remitting MS., Results: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNbeta-1a-treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline., Conclusion: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.

Aim: To compare the onset of action of the local antacid Maalox and the systemic H2-antagonist ranitidine, during 'on demand' ambulant treatment of a single heartburn episode, using a randomized, parallel group, double-blind, double-dummy design., Methods: Subjects with self-perceived heartburn without known gastrointestinal disease or interfering treatments were selected with questionnaires. The study was performed unsupervised, whenever heartburn required medication. An electronic patient diary gave instructions when to take study medication, and provided visual analogue scales and five-item relief ratings for heartburn, at frequent time intervals activated by an alarm-clock., Results: After a study of the natural history of heartburn and the feasibility of the study procedures in 23 patients, 49 subjects took Maalox and 45 ranitidine. Half of these experienced meaningful heartburn relief within 19 min after Maalox, and within 70 min after ranitidine. One hour after intake, the average heartburn relief score was 3.43 in the Maalox group and 3.04 in the ranitidine group (3 means 'slight improvement' and 4 'strong improvement'). Heartburn was similar in both groups after 3 h., Conclusions: Maalox provides faster relief of heartburn than ranitidine. Heartburn can be assessed frequently and reliably under ambulant conditions using an electronic patient diary.

We have obtained a current profile of multiple sclerosis York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.

Objective: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon beta-1a (Avonex)., Methods: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area., Results: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement., Conclusion: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

The cytokines, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2) are important endogenous proinflammatory proteins and have been linked to disease activity in multiple sclerosis. In this study, we use flow cytometric methodology to compare the secretion of IFN-gamma, IL-2, and TNF-alpha from peripheral blood-derived T cells of multiple sclerosis patients to the secretion in healthy controls. The percentages of IFN-gamma, IL-2, and TNF-alpha secreting cells are not significantly different between multiple sclerosis patients and controls. However, the TNF-alpha secreting CD3 cell percentage is correlated with the IFN-gamma and IL-2 secreting CD3 cell percentages in multiple sclerosis patients. In the controls, only the TNF-alpha secreting CD3 cell percentage is correlated with IFN-gamma. These findings show that correlated secretion of cytokines occurs in multiple sclerosis and suggest that concerted intercytokine interactions may play an important role in the disease.

Leber's hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis due to multiple sclerosis (MS). For several decades an association of LHON and MS has been suspected, and within the past 7 years the LHON nucleotide (nt)-3460 and nt-11778 mtDNA mutations have been identified in several patients with MS-like phenotypes. To further study this association, we tested 42 index patients with clinically definite, familial MS for the LHON mtDNA mutations at nt-3460, nt-11778, and nt-14484. No patients had a pathogenic LHON mtDNA mutation; however, two MS patients with unilateral optic neuritis harbored the nt-15257 mtDNA polymorphism that was reported originally as a pathogenic LHON mutation. Several investigators have shown evidence that the nt-15257 mtDNA mutation is not primarily pathogenic. Therefore, we conclude that pathogenic LHON mtDNA mutations are absent or rare in unselected patients with familial, clinically definite MS (95% confidence intervals for each of the negative mutations 0-7.0%).

Background and Objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities., Methods: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment., Results: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups., Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physician-based composite of BBT, 9HPT, and TA was of comparable sensitivity (P = 0.013) in discriminating sustained treatment failure as the EDSS alone (P = 0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P = 0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

Background: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment., Objectives: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients., Methods: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b., Results: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB., Conclusions: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.

Objective: To assess the concentration of ketoprofen, after topical plaster application, in various tissues in relation to plasma levels in 60 patients undergoing surgery for Achilles or patellar tendinopathy; and to analyze whether tissues act as a reservoir of ketoprofen, by evaluating tissue concentrations in relation to plasma concentration at various time points after removal of the plaster. No attempt was made to study the clinical effect of treatment per se., Methods: In random order to patients applied 30 mg plasters once daily for 5 consecutive days (n = 30), or took a single oral dose 50 mg (n = 30) before surgery. Tissue samples of skin, subcutaneous fat, tendon sheath, and tendon, and plasma were collected intraoperatively at 0, 6 and 14 hours after removal of the 5th plaster, and at 2, 6, and 14 hours after oral intake. Ketoprofen concentration was determined by a validated GC/MS method. The low limit of quantification was 0.5 ng/ml plasma and 0.5 ng/50 mg tissues., Results: High concentrations of ketoprofen were observed in fat, tendon sheath, and tendon after topical applications, whereas plasma levels of ketoprofen were low., Conclusion: Ketoprofen attains high concentrations in subcutaneous tissues after multiple topical applications. Subcutaneous tissues appear to act as a reservoir of ketoprofen.

Background and Objective: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance., Methods: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial., Results: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment., Conclusions: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

We found 42 of 74 patients (57%) with isolated monosymptomatic optic neuritis to have 1 to 20 brain lesions, by magnetic resonance imaging (MRI). All of the brain lesions were clinically silent and had characteristics consistent with multiple sclerosis (MS). None of the patients had ever experienced neurologic symptoms prior to the episode of optic neuritis. During 5.6 years of follow-up, 21 patients (28%) developed definite MS on clinical grounds. Sixteen of the 21 converting patients (76%) had abnormal MRIs; the other 5 (24%) had MRIs that were normal initially (when they had optic neuritis only) and when repeated after they had developed clinical MS in 4 of the 5. Of the 53 patients who have not developed clinically definite MS, 26 (49%) have abnormal MRIs and 27 (51%) have normal MRIs. The finding of an abnormal MRI at the time of optic neuritis was significantly related to the subsequent development of MS on clinical grounds, but interpretation of the strength of that relationship must be tempered by the fact that some of the converting patients had normal MRIs and approximately half of the patients who did not develop clinical MS had abnormal MRIs. We found that abnormal IgG levels in the cerebrospinal fluid correlated more strongly than abnormal MRIs with the subsequent development of clinically definite MS.

A polymorphic (TGCG)n, tetranucleotide repeat was discovered juxtaposed to the (GT)n dinucleotide repeat that comprises the tumor necrosis factor a microsatellite (TNF) located telomeric to the tumor necrosis factor/lymphotoxin gene cluster. The degree of complexity of this compound tetra-,dinucleotide microsatellite consists of 16 potential alleles of combined length ranging from 24 to 54 bp. The pattern of frequencies of individual alleles belonging to the compound TNFa microsatellite was established from 52 healthy volunteers and was found to be highly heterogeneous. The data diverges significantly from previously published statistics that recognized only a simple variable dinucleotide tandem repeat. The newly recognized compound tetra-, dinucleotide TNFa microsatellite polymorphism establishes a more accurate genetic basis to explore potential linkage with disease susceptibility genes located within this region of the class III major histocompatibility complex. In addition, variable tumor necrosis factor and lymphotoxin production may reflect the more complex polymorphic nature of this microsatellite region. Finally, compound microsatellites probably exist elsewhere, throughout the human genome. Recognition of their presence may have a considerable impact on the validity of past and future microsatellite-based genetic analyses.

1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic tension-type headache, using a double-blind, randomized, parallel group design. 2. A total of 166 patients with headache compatible with episodic tension-type headache and no refractory headaches or contraindications to NSAIDs were contacted by advertisements and selected by questionnaires. Patients performed the study at home, using an electronic diary for headache assessment, with a form to allow comments and corrections. Visual analogue scales (VAS 10 cm) of headache severity, five-item headache relief rating (HRR) scales, and time of intake of 'escape' analgesics were scored regularly, for 4 h following intake of trial medication. 3. VAS-scores (n = 1407) and HRRs (n = 452) were returned by 159 patients. Of these scores, 1.5% were inadvertently omitted from the electronic diary or modified on the comment forms. 4. Headache (VAS and HRR) improved more with all three NSAIDs than with placebo, although the effect of ibuprofen was significant for HRR only. After 2 and 4 h respectively, the reduction in VAS-ratios was 17 and 19% with placebo, 18 and 53% with ibuprofen 200 mg, 41 and 61% with ketoprofen 25 mg, and 47 and 59% with ketoprofen 50 mg. After 4 h, headache improved strongly (highest HRR) in 18% of patients on placebo, 39% on ibuprofen 200 mg, 62% on ketoprofen 25 mg, and 55% on ketoprofen 50 mg. Headache disappeared completely (VAS-score = 0) in one patient (3%) with placebo (after 180 min), 10% with ibuprofen 200 mg (average 211 min), 18% with ketoprofen 25 mg (159 min), and 28% with ketoprofen 50 mg (146 min). 5. The effects of ketoprofen 50 mg were more pronounced than those of ibuprofen 200 mg, which seemed to start later. Ketoprofen 25 mg and 50 mg were very similar, suggesting a maximal effect of the lower dose. Mild to moderate adverse events were reported by 9% of the patients, half of which occurred with ketoprofen 50 mg. Treatment of headache with ketoprofen can start with 25 mg, and possibly less. 6. Although a direct comparative study would be necessary to determine the relative benefits of the novel electronic patient diaries over traditional paper-and-pencil methods, this study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data. Electronic patient diaries appear to be an important new attribute for the efficacy assessment of self-medicated drugs.

Objective: To assess the safety, tolerability and efficacy of low-dose ketoprofen (75-150 mg daily for 5 to 15 days) in a general practice setting., Design: Open label, non-controlled study of ketoprofen 25 mg tablets in the treatment of pain in ENT diseases, dysmenorrhoea, and musculoskeletal disorders., Setting: General practice, 600 investigators, Subjects: Four thousand and sixty-eight patients, aged 13-93 years, mean 42.3 years, 1009 with ENT diseases (mean age 38.8 (13-83) years, 53% female), 978 with dysmenorrhoea (mean age 30.3 (13-60) years, 100% female), 2081 with musculoskeletal disorders (mean age 49.6 (16-93) years, 54% female)., Main Outcome Measures: Occurrence of adverse events, on patient and physician evaluation; dose and duration of treatment prescribed/taken (diary); global evaluation of efficacy by patient and physician., Result: Twenty-two patients were lost to follow-up (<1%); dose effectively taken was lower than prescribed (3.3 versus 3.6 tablets/day); treatment was stopped prematurely in 3.3% of patients because of adverse events, in 17.1% because of early success of therapy. Gastrointestinal adverse events (AE) were the most frequent (76%) of AE), occurring in 10% of patients. They were more frequent in patients with musculoskeletal pain, who were older and had more associated diseases. Five patients were hospitalized, two for preplanned hospitalizations, the others for one asthma attack, one worsening of low back pain, and one angina attack, none attributed to treatment by the GP. None of the AE was life-threatening. Identified risk factors for AE were age and previous medical history, especially of gastrointestinal disorders., Conclusions: Good quality large scale studies with little or no loss to follow-up can be done in a general practice setting. At the dose used, ketoprofen was generally well tolerated, and used at a lower dose than prescribed, it was not associated with severe or new side-effects. The results of this study could justify its use in self-medication in these indications.

The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-beta-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 x 10(6) IU (30 micrograms) of IFN-beta-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0-3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-beta-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

In this pilot study hypnosis was used in an attempt to provide evidence of a psychogenic component of pseudo-epileptic seizures. The criterion for psychogenesis was the reversal of the amnesia, which is often present in epileptic- and pseudo-epileptic seizures. The technique has been validated by a semi-blind referral of cases for analysis after the clinician had been able to make a firm diagnosis based on electro-encephalic corroboration of the nature of the seizure. In eight out of nine patients (of the original 13 patients, three patients dropped out and one patient was not evaluable), the experimental diagnosis corresponded with the clinical diagnosis. As pseudo-epileptic seizures can be characterized by their dissociative nature, a reasonable hypothesis is that patients with pseudo-epileptic seizures are more responsive to hypnosis than patients with epileptic seizures. Measurements of hypnotizability among seven patients with epileptic seizures and six patients with pseudo-epileptic seizures supported this supposition.

We studied androgen receptor function in cultured scrotal skin fibroblasts from eight subjects with X-linked spinal and bulbar muscular atrophy (SBMA) (Kennedy's syndrome) from four families. The neuromuscular and endocrine features were similar in all patients. High-affinity dihydrotestosterone binding (Bmax) was decreased in three patients from one family (average, 11.1 fmol/mg) similar to values in subjects with androgen resistance syndromes. Bmax was normal in five SBMA patients from three other families (average, 26.0 fmol/mg). This finding provides direct evidence for abnormal androgen receptor function in some patients with SBMA. There was some correlation between severity of neuromuscular and endocrine dysfunction, providing further evidence that the two types of manifestations are related.