Showing papers by "Mayo Clinic published in 1999"

Mild Cognitive Impairment: Clinical Characterization and Outcome

Abstract: Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion

Abstract: The B7 family members B7-1 and B7-2 interact with CD28 and constitute an essential T-cell co-stimulatory pathway in the initiation of antigen-specific humoral and cell-mediated immune response. Here, we describe a third member of the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or ICOS (inducible co-stimulator). Ligation of B7-H1 co-stimulated T-cell responses to polyclonal stimuli and allogeneic antigens, and preferentially stimulated the production of interleukin-10. Interleukin-2, although produced in small amounts, was required for the effect of B7-H1 co-stimulation. Our studies thus define a previously unknown co-stimulatory molecule that may be involved in the negative regulation of cell-mediated immune responses.

Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta

Abstract: In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

The clinical course of neuromyelitis optica (Devic's syndrome)

Abstract: Objectives: To evaluate the spectrum of neuromyelitis optica (NMO), including characteristics of the index events (optic neuritis [ON]) and myelitis), neuroimaging, CSF, and serologic studies, and to evaluate the long-term course. Methods: Review of 71 patients with NMO evaluated at the Mayo Clinic between 1950 and 1997. Results: NMO was either monophasic or relapsing. Patients with a monophasic course (n = 23) usually presented with rapidly sequential index events (median 5 days) with moderate recovery. Most with a relapsing course (n = 48) had an extended interval between index events (median 166 days) followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. Most relapsing patients developed severe disability in a stepwise manner, and one-third died because of respiratory failure. Features of NMO distinct from “typical” MS included >50 cells/mm 3 in CSF (often polymorphonuclear), normal initial brain MRI, and lesions extending over three or more vertebral segments on spinal cord MRI. Conclusions: Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.

Predictors of Recurrence After Deep Vein Thrombosis and Pulmonary Embolism: A Population-Based Cohort Study

Abstract: Background The appropriate duration of oral anticoagulation after a first episode of venous thromboembolism (VTE) is uncertain and depends upon VTE recurrence rates. Objective To estimate VTE recurrence rates and determine predictors of recurrence. Methods Patients in Olmsted County, Minnesota, with a first lifetime deep vein thrombosis or pulmonary embolism diagnosed during the 25-year period from 1966 through 1990 (N = 1719) were followed forward in time through their complete medical records in the community for first VTE recurrence. Results Four hundred four patients developed recurrent VTE during 10 198 person-years of follow-up. The overall (probable/definite) cumulative percentages of VTE recurrence at 7, 30, and 180 days and 1 and 10 years were 1.6% (0.2%), 5.2% (1.4%), 10.1% (4.1%), 12.9% (5.6%), and 30.4% (17.6%), respectively. The risk of recurrence was greatest in the first 6 to 12 months after the initial event but never fell to zero. Independent predictors of first overall VTE recurrence included increasing age and body mass index, neurologic disease with paresis, malignant neoplasm, and neurosurgery during the period from 1966 through 1980. Independent predictors of first probable/definite recurrence included diagnostic certainty of the incident event and neurologic disease in patients with hospital-acquired VTE. Recurrence risk was increased by malignant neoplasm but varied with concomitant chemotherapy, patient age and sex, and study year. Conclusions Venous thromboembolism recurs frequently, especially within the first 6 to 12 months, and continues to recur for at least 10 years after the initial VTE. Patients with VTE with neurologic disease and paresis or with malignant neoplasm are at increased risk for recurrence, while VTE patients with transient or reversible risk factors are at less risk.

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

Abstract: Objective: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer’s disease (AD) in older patients with a mild cognitive impairment (MCI). Background: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly.Patients:— Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer’s Disease Center/Alzheimer’s Disease Patient Registry. Methods: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. Results: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models—using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension—the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. Conclusion: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.

Efficacy of Bilateral Prophylactic Mastectomy in Women with a Family History of Breast Cancer

Abstract: Background Options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic mastectomy. The data on the outcomes for surveillance and prophylactic mastectomy are incomplete. Methods We conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. The women were divided into two groups — high risk and moderate risk — on the basis of family history. A control study of the sisters of the high-risk probands and the Gail model were used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. Results We identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: 214 at high risk and 425 at moderate risk. The median length of follow-up was 14 years. The median age at prophylactic mastectomy was 42 years. According to the Gail model, 37.4 breast cancers wer...

Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.

Abstract: Background Although aortic-valve stenosis is clearly associated with adverse cardiovascular outcomes, it is unclear whether valve sclerosis increases the risk of cardiovascular events. Methods We assessed echocardiograms obtained at base line from 5621 men and women 65 years of age or older who were enrolled in a population-based prospective study. On echocardiography, the aortic valve was normal in 70 percent (3919 subjects), sclerotic without outflow obstruction in 29 percent (1610), and stenotic in 2 percent (92). The subjects were followed for a mean of 5.0 years to assess the risk of death from any cause and of death from cardiovascular causes. Cardiovascular morbidity was defined as new episodes of myocardial infarction, angina pectoris, congestive heart failure, or stroke. Results There was a stepwise increase in deaths from any cause (P for trend, <0.001) and deaths from cardiovascular causes (P for trend, <0.001) with increasing aortic-valve abnormality; the respective rates were 14.9 and 6.1 per...

Development of a multiple sclerosis functional composite as a clinical trial outcome measure

Abstract: The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Cinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

A role for ATR in the DNA damage-induced phosphorylation of p53

Abstract: Phosphorylation at Ser-15 may be a critical event in the up-regulation and functional activation of p53 during cellular stress. In this report we provide evidence that the ATM–Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells. Overexpression of catalytically inactive ATR (ATRki) in human fibroblasts inhibited Ser-15 phosphorylation in response to γ-irradiation and UV light. In γ-irradiated cells, ATRki expression selectively interfered with late-phase Ser-15 phosphorylation, whereas ATRki blocked UV-induced Ser-15 phosphorylation in a time-independent manner. ATR phosphorylated p53 at Ser-15 and Ser-37 in vitro, suggesting that p53 is a target for phosphorylation by ATR in DNA-damaged cells.

Liposomal Amphotericin B for Empirical Therapy in Patients with Persistent Fever and Neutropenia

Abstract: Background In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. Methods We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. Results The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P Conclusions Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.

Caveolins, liquid-ordered domains, and signal transduction.

Abstract: Caveolae were originally identified as flask-shaped invaginations of the plasma membrane in endothelial and epithelial cells (14). Prior to the development of biochemical methods for their purification, caveolae were thought to principally mediate the transcellular movement of molecules (101, 145). Recently, the development of novel purification procedures has greatly expanded our knowledge regarding the putative functions of caveolae in vivo. In this review, we seek to update the working definition of caveolae, describe the functional roles of the caveolin gene family, and summarize the evidence that supports a role for caveolae as mediators of a number of cellular signaling processes.

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Abstract: Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-γ–inducible protein of 10 kDa (IP-10); monokine induced by interferon-γ (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine–chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

Mechanical and Chemical Unfolding of a Single Protein: A Comparison

Abstract: Is the mechanical unraveling of protein domains by atomic force microscopy (AFM) just a technological feat or a true measurement of their unfolding? By engineering a protein made of tandem repeats of identical Ig modules, we were able to get explicit AFM data on the unfolding rate of a single protein domain that can be accurately extrapolated to zero force. We compare this with chemical unfolding rates for untethered modules extrapolated to 0 M denaturant. The unfolding rates obtained by the two methods are the same. Furthermore, the transition state for unfolding appears at the same position on the folding pathway when assessed by either method. These results indicate that mechanical unfolding of a single protein by AFM does indeed reflect the same event that is observed in traditional unfolding experiments. The way is now open for the extensive use of AFM to measure folding reactions at the single-molecule level. Single-molecule AFM recordings have the added advantage that they define the reaction coordinate and expose rare unfolding events that cannot be observed in the absence of chemical denaturants.

Role of Nonexercise Activity Thermogenesis in Resistance to Fat Gain in Humans

Abstract: Humans show considerable interindividual variation in susceptibility to weight gain in response to overeating. The physiological basis of this variation was investigated by measuring changes in energy storage and expenditure in 16 nonobese volunteers who were fed 1000 kilocalories per day in excess of weight-maintenance requirements for 8 weeks. Two-thirds of the increases in total daily energy expenditure was due to increased nonexercise activity thermogenesis (NEAT), which is associated with fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold differences in fat storage that occurred and directly predicted resistance to fat gain with overfeeding (correlation coefficient = 0.77, probability < 0.001). These results suggest that as humans overeat, activation of NEAT dissipates excess energy to preserve leanness and that failure to activate NEAT may result in ready fat gain.

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice

Abstract: We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Biliary tract cancers

Abstract: In the United States, an estimated 20,000 new cases of liver and biliary tract cancer are diagnosed annually.1 Biliary tract cancer is the second most common primary hepatobiliary cancer, after hepatocellular cancer. Approximately 7500 new cases of biliary tract cancer are diagnosed per year; about 5000 of these are gallbladder cancer, and between 2000 and 3000 are bile-duct cancers.1 Biliary tract cancers have traditionally been divided into cancers of the gallbladder, the extrahepatic bile ducts, and the ampulla of Vater, whereas intrahepatic bile-duct cancers have been classified as primary liver cancers.2 The term “cholangiocarcinoma” was originally intended to refer only . . .

Simulation Technology for Health Care Professional Skills Training and Assessment

Abstract: Changes in medical practice that limit instruction time and patient availability, the expanding options for diagnosis and management, and advances in technology are contributing to greater use of simulation technology in medical education. Four areas of high-technology simulations currently being used are laparoscopic techniques, which provide surgeons with an opportunity to enhance their motor skills without risk to patients; a cardiovascular disease simulator, which can be used to simulate cardiac conditions; multimedia computer systems, which includes patient-centered, casebased programs that constitute a generalist curriculum in cardiology; and anesthesia simulators, which have controlled responses that vary according to numerous possible scenarios. Some benefits of simulation technology include improvements in certain surgical technical skills, in cardiovascular examination skills, and in acquisition and retention of knowledge compared with traditional lectures. These systems help to address the problem of poor skills training and proficiency and may provide a method for physicians to become self-directed lifelong learners.

The Diagnosis and Incidence of Allergic Fungal Sinusitis

Abstract: Objectives To reevaluate the current criteria for diagnosing allergic fungal sinusitis (AFS) and determine the incidence of AFS in patients with chronic rhinosinusitis (CRS). Methods This prospective study evaluated the incidence of AFS in 210 consecutive patients with CRS with or without polyposis, of whom 101 were treated surgically. Collecting and culturing fungi from nasal mucus require special handling, and novel methods are described. Surgical specimen handling emphasizes histologie examination to visualize fungi and eosinophils in the mucin. The value of allergy testing in the diagnosis of AFS is examined. Results Fungal cultures of nasal secretions were positive in 202 (96%) of 210 consecutive CRS patients. Allergic mucin was found in 97 (96%) of 101 consecutive surgical cases of CRS. Allergic fungal sinusitis was diagnosed in 94 (93%) of 101 consecutive surgical cases with CRS, based on histopathologic findings and culture results. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of AFS patients. Conclusion The data presented indicate that the diagnostic criteria for AFS are present in the majority of patients with CRS with or without polyposis. Since the presence of eosinophils in the allergic mucin, and not a type I hypersensitivity, is likely the common denominator in the pathophysiology of AFS, we propose a change in terminology from AFS to eosinophilic fungal rhinosinusitis.

A family of mammalian Na + -dependent L -ascorbic acid transporters

Abstract: Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which it serves to maintain prosthetic metal ions in their reduced forms (for example, Fe2+, Cu+), and for scavenging free radicals in order to protect tissues from oxidative damage. The facilitative sugar transporters of the GLUT type can transport the oxidized form of the vitamin, dehydroascorbic acid, but these transporters are unlikely to allow significant physiological amounts of vitamin C to be taken up in the presence of normal glucose concentrations, because the vitamin is present in plasma essentially only in its reduced form. Here we describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from rat complementary DNA libraries, as the first step in investigating the importance of L-ascorbic acid transport in regulating the supply and metabolism of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high-affinity L-ascorbic acid transport that is stereospecific and is driven by the Na+ electrochemical gradient. Despite their close sequence homology and similar functions, the two isoforms of the transporter are discretely distributed: SVCT1 is mainly confined to epithelial systems (intestine, kidney, liver), whereas SVCT2 serves a host of metabolically active cells and specialized tissues in the brain, eye and other organs.

Mechanical unfolding intermediates in titin modules.

Abstract: The modular protein titin, which is responsible for the passive elasticity of muscle, is subjected to stretching forces. Previous work on the experimental elongation of single titin molecules has suggested that force causes consecutive unfolding of each domain in an all-or-none fashion1,2,3,4,5,6. To avoid problems associated with the heterogeneity of the modular, naturally occurring titin, we engineered single proteins to have multiple copies of single immunoglobulin domains of human cardiac titin7. Here we report the elongation of these molecules using the atomic force microscope. We find an abrupt extension of each domain by ∼7 A before the first unfolding event. This fast initial extension before a full unfolding event produces a reversible ‘unfolding intermediate’. Steered molecular dynamics8,9 simulations show that the rupture of a pair of hydrogen bonds near the amino terminus of the protein domain causes an extension of about 6 A, which is in good agreement with our observations. Disruption of these hydrogen bonds by site-directed mutagenesis eliminates the unfolding intermediate. The unfolding intermediate extends titin domains by ∼15% of their slack length, and is therefore likely to be an important previously unrecognized component of titin elasticity.

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.

Abstract: There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

Electron Beam Computed Tomographic Coronary Calcium Scanning: A Review and Guidelines for Use in Asymptomatic Persons

Abstract: Coronary artery disease is the No. 1 cause of death in the developed world. Effective means of treatment such as drug therapy to lower cholesterol levels are available, but clinical application to patients at highest risk remains imprecise. Electron beam computed tomography (EBCT) has been suggested as a means to diagnose subclinical coronary disease and facilitate risk stratification, but no current interpretive consensus exists in clinical practice. We critically reviewed current, pertinent literature regarding EBCT coronary calcium scanning from a clinical perspective and, in particular, studies that evaluated it as a measure of atherosclerotic coronary disease. Additionally, we reviewed studies that quantified the EBCT "calcium score" in relationship to coronary heart disease events. The available data suggest that the EBCT calcium score can help identify persons at higher than anticipated risk of future coronary events: the greater the EBCT coronary calcium score, the greater the extent of atherosclerotic plaque disease. Based on the literature review, we offer EBCT interpretation guidelines as they relate to drug therapy and risk reduction in asymptomatic persons with borderline cholesterol levels. Considerable evidence shows that coronary calcium is specific for atherosclerotic plaque and that it can be sensitively detected and accurately quantified by using EBCT. The coronary calcium score can help guide initiation of clinical prevention programs as part of a risk stratification and management scheme aimed at improving outcomes in patients determined to be at highest risk of coronary disease for their respective age and gender.

Nonpharmacologic Treatment of Chronic Insomnia

Abstract: This paper reviews the evidence regarding the efficacy of nonpharmacological treatments for primary chronic insomnia. It is based on a review of 48 clinical trials and two meta-analyses conducted by a task force appointed by the American Academy of Sleep Medicine to develop practice parameters on non-drug therapies for the clinical management of insomnia. The findings indicate that nonpharmacological therapies produce reliable and durable changes in several sleep parameters of chronic insomnia sufferers. The data indicate that between 70% and 80% of patients treated with nonpharmacological interventions benefit from treatment. For the typical patient with persistent primary insomnia, treatment is likely to reduce the main target symptoms of sleep onset latency and/or wake time after sleep onset below or near the 30-min criterion initially used to define insomnia severity. Sleep duration is also increased by a modest 30 minutes and sleep quality and patient's satisfaction with sleep patterns are significantly enhanced. Sleep improvements achieved with these behavioral interventions are sustained for at least 6 months after treatment completion. However, there is no clear evidence that improved sleep leads to meaningful changes in daytime well-being or performance. Three treatments meet the American Psychological Association (APA) criteria for empirically-supported psychological treatments for insomnia: Stimulus control, progressive muscle relaxation, and paradoxical intention; and three additional treatments meet APA criteria for probably efficacious treatments: Sleep restriction, biofeedback, and multifaceted cognitive-behavior therapy. Additional outcome research is needed to examine the effectiveness of treatment when it is implemented in clinical settings (primary care, family practice), by non-sleep specialists, and with insomnia patients presenting medical or psychiatric comorbidity.

Association of an extended haplotype in the tau gene with progressive supranuclear palsy.

Abstract: We describe two extended haplotypes that cover the human tau gene. In a total of approximately 200 unrelated caucasian individuals there is complete disequilibrium between polymorphisms which span the gene (which covers approximately 100 kb of DNA). This suggests that the establishment of the two haplotypes was an ancient event and either that recombination is suppressed in this region, or that recombinant genes are selected against. Furthermore, we show that the more common haplotype (H1) is significantly over-represented in patients with progressive supranuclear palsy (PSP), extending earlier reports of an association between an intronic dinucleotide polymorphism and PSP.

Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis.

Abstract: Osteoporosis is a serious complication of systemic glucocorticoid use. However, while glucocorticoids increase bone resorption in vitro and in vivo, the mechanism(s) of this effect are at present unclear. Recent studies have identified the osteoprotegerin (OPG) ligand (OPG-L) as the final effector of osteoclastogenesis, an action that is opposed by the soluble neutralizing receptor, OPG. Thus, we assessed glucocorticoid regulation of OPG and OPG-L in various human osteoblastic lineage cells using Northern analysis, RT-PCR, and ELISA. Dexamethasone inhibited constitutive OPG messenger RNA (mRNA) steady-state levels by 70 ‐90% in primary (MS) and immortalized stromal cells (hMS), primary trabecular osteoblasts (hOB), immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). In hFOB cells, dexamethasone inhibited constitutive OPG mRNA steady-state levels in a dose- and time-dependent fashion by 90%, and also suppressed cytokine-stimulated OPG mRNA steady-state levels. Dexamethasone-induced inhibition of OPG mRNA levels was not affected by the protein synthesis inhibitor, cycloheximide, and was shown to be due to inhibition of OPG gene transcription using a nuclear run-on assay. Moreover, dexamethasone also dose dependently (10 210 M‐10 27 M) inhibited constitutive OPG protein concentrations in the conditioned medium of hFOB cells from 2.59 6 0.02 ng/ml (control) to 0.30 6 0.01 ng/ml (88% inhibition; P , 0.001 by ANOVA). Concurrently, dexamethasone stimulated OPG-L mRNA steady-state levels in MS and hFOB cells by 2- and 4-fold, respectively. Treatment of murine marrow cultures with conditioned medium harvested from dexamethasone-treated MG-63 cells increased tartrate-resistant acid phosphatase (TRAP) activity by 54% (P , 0.005) compared with medium harvested from control-treated cells (in the presence of OPG-L and macrophage colony-stimulating factor). Moreover, dexamethasone (10 28 M) promoted osteoclast formation in vitro, as assessed by a 2.5-fold increase of TRAP activity in cell lysates (P , 0.001) and the appearance of TRAP-positive multinucleated cells. Our data are thus consistent with the hypothesis that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating OPG-L production by osteoblastic lineage cells, thereby enhancing bone resorption. (Endocrinology 140: 4382‐ 4389, 1999)