Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats.

RATIONALE: Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease would be of great benefit. OBJECTIVES: The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus. MATERIALS AND METHODS: Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus. RESULTS: S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn-superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986. CONCLUSIONS: Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.

Osteoarthritis: new insights. Part 2: treatment approaches.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, estrogen use, and bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. These risk factors are particularly important in the weight-bearing joints, and modifying them may help prevent osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 2 of a two-part summary of a National Institutes of Health conference that brought together experts in osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 2 focuses on treatment approaches; evidence for the efficacy of commonly used oral therapies is reviewed and information on alternative therapies, including nutriceuticals and acupuncture, is presented. Biomechanical interventions, such as exercise and bracing, and behavioral interventions directed toward enhancing self-management are reviewed. Current surgical approaches are described and probable future biotechnology-oriented approaches to treatment are suggested.

Osteoarthritis: new insights. Part 1: the disease and its risk factors.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weight-bearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability.

Spondyloarthropathy in the community: differences in severity and disease expression in Alaskan Eskimo men and women.

OBJECTIVES: To determine the relative severity and compare the clinical expression of spondyloarthropathy (SpA) in men and women. METHODS: A clinical study was conducted in 43 women and 40 men who made up 80% of all individuals identified as having SpA in a community-wide epidemiologic study of Alaskan Eskimos. The study included interviews, physical, laboratory, radiographic and electrocardiographic examinations, record reviews, and functional assessments. A measure of relative severity was developed to evaluate disease impact in individual patients. The results in men and women were compared. RESULTS: No significant differences between men and women were found in many features, including the age of onset, frequency of inflammatory joint swelling or inflammatory back pain, physical signs of sacroiliitis, presence of skin changes, or positive family history of SpA. Women were less likely to have sacroiliac joint fusion, advanced spinal changes, uveitis, severe cardiac conduction and valvular abnormalities, and elevated erythrocyte sedimentation rates. According to our relative severity measure, a smaller proportion of women had severe disease than men. CONCLUSION: Although as many women as men were affected by SpA in the communities studied, severe disease was seen more often in men and a number of disease manifestations were more frequent or more marked in men. These discrepancies in disease severity and expression may contribute to the underdiagnosis of SpA in women and the long standing impression that SpA is a disease predominantly of men.

Spondyloarthropathy in the community: clinical syndromes and disease manifestations in Alaskan Eskimo populations.

OBJECTIVE: To define the clinical spectrum and disease manifestations of spondyloarthropathy (SpA) as seen in a community, rather than a referral setting. METHODS: Eighty percent (83/104) of all individuals identified as having SpA in a community wide epidemiologic study of Alaskan Eskimos and 83 age and sex matched controls from the same regions participated in a 5 year clinical study. The study included baseline and followup interviews, physical, radiographic, and electrocardiographic examinations, record reviews, and functional assessment. The medical records of an additional 83 age and sex matched controls were reviewed and followed over the same 5 year period. RESULTS: The spectrum of disease varied from very mild undifferentiated SpA (USpA) to incapacitating ankylosing spondylitis (AS). Most cases were mild. Overlapping clinical features were common in the different syndromes; 10% of the cases met more than 1 set of disease criteria. Axial signs and symptoms were more frequent in patients with AS, but occurred in over half of the patients with USpA and reactive arthritis (ReA) also. Peripheral joint involvement was noted in 85% of the AS cases, usually early in the course of disease. The patterns of joint involvement and enthesopathy were similar in SpA subjects with different syndromes and significantly different from those in control subjects. Patients with AS had a higher frequency of uveitis and of aortic root disease than patients with other syndromes. CONCLUSION: The results illustrate the extent of shared clinical features in the different SpA syndromes, and describe the frequency of different features associated with SpA in patients and matched controls in a community setting. ReA and USpA were more prevalent and less severe than AS in these populations.

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.

OBJECTIVE: To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). METHODS: The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. RESULTS: Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. CONCLUSION: Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.

A comparison of patients with spondyloarthropathy seen in specialty clinics with those identified in a communitywide epidemiologic study. Has the classic case misled us?

BACKGROUND: Undiagnosed cases of seronegative spondyloarthropathy (Spa) are often observed during epidemiologic studies. OBJECTIVE: To determine the extent of and the reasons for the underdiagnosis of Spa. METHODS: We studied 2 groups of Alaskan native patients with Spa using a standardized protocol that included an interview, physical examination, medical record review, and radiographic and laboratory examinations. One group consisted of patients identified in a communitywide epidemiologic study; the other group consisted of patients from related but geographically separate populations who had been diagnosed by a specialist in the hospital or a specialty clinic. All cases met the current classification criteria for Spa. The clinical and demographic features of the cases in the 2 groups were compared. RESULTS: Fifty-five (72%) of the 76 community cases that we identified in the epidemiologic study had not been diagnosed previously as Spa. Among the undiagnosed patients were 34 (94%) of the 36 women, 11 (65%) of the 17 patients with ankylosing spondylitis, 12 (36%) of the 33 patients with reactive arthritis, and 24 (100%) of those with undifferentiated Spa. The community and specialty clinic patient groups were similar in age of onset of joint and back pain and in overall symptoms. The specialty clinic group had a higher proportion of men, more severe disease, and a higher frequency of iritis. CONCLUSIONS: The diagnosis of Spa was missed more often than not in the primary care setting, probably because most of the cases were of mild or moderate severity and did not fit the classic descriptions of spondyloarthropathic disorders. The higher proportion of men among the specialty clinic cases probably reflects provider expectation as well as a slightly milder disease course in women.

Metered dose inhalers III: Metaproterenol sulphate; particle size distribution and dose uniformity.

Three American products and one Canadian product were examined for content uniformity and particle size distribution. The results showed that not all products performed equally well. Some of the products exhibited high sprays early in the canister lifetime and all products demonstrated loss of prime. The particle size distributions were determined using the Andersen cascade impactor (USP Induction Port) and the fine particle fraction was determined using the twin impinger. The results showed that three of the four products had similar particle size distribution profiles. Both the Andersen cascade impactor and the twin impinger yielded the same trends in the amount of drug substance delivered to the fine particle fraction.

Class I HLA antigens in spondyloarthropathy: observations in Alaskan Eskimo patients and controls.

OBJECTIVE: To assess the role of HLA-B27 and other class I histocompatibility antigens in overall risk and clinical manifestations of spondyloarthropathy (SpA) in Alaskan Eskimos. METHODS: Class I antigens were studied in 104 patients with SpA and in 111 controls. The frequencies of HLA-A, B, and Cw antigens were determined in patients with SpA with various clinical manifestations and compared to frequencies observed in controls. RESULTS: Only HLA-B27 differed significantly in cases and controls. Except for B27, no association of particular antigens with specific syndromes or disease features was found. Patients with B27 had more extraarticular manifestations than patients who lacked B27 antigen. Patients putatively homozygous for B27 did not appear to have more severe disease than those who were heterozygotic. B27 was most closely associated with ankylosing spondylitis [odds ratio (OR) = 210], less so with reactive arthritis (OR = 12.9) and undifferentiated SpA (OR = 4.6). CONCLUSION: Observations in other population groups that implicated B27 cross reactive group (CREG) and other A, B, and Cw antigens as risk factors for developing SpA were not confirmed in Alaskan Eskimos. Nor were CREG or other B antigens either alone or in combination with B27 associated with specific clinical syndromes. Only HLA-B27 was strongly associated with disease and with extraarticular manifestations.

Spondylarthropathic diseases in indigenous circumpolar populations of Russia and Alaska.

AIMS: To compare the nature and frequency of spondylarthropathy in geographically separated but genetically related populations with a high prevalence of HLA-B27. METHODS: Using a common questionnaire and disease criteria, cases were ascertained through cross-sectional community surveys in Russia and by examination and study of possible cases identified through rheumatic disease registries and the Native Health Service's computerized patient care data system in Alaska. RESULTS: Similar overall prevalences of spondyloarthropathy (2.0-3.4%) and a similar spectrum of disease were found, including reactive arthritis, ankylosing spondylitis and undifferentiated spondylarthropathy. Psoriatic arthritis was very rare. CONCLUSION: No predisposition to one particular form of spondyloarthropathy was observed; genetic and microbial settings for a spectrum of disease were present. Among adults positive for the presence of HLA-B27 the prevalence of all types of spondylarthropathies was estimated to be 4.5%, all populations combined, and the prevalence of AS was estimated to be 1.6%.

Spondyloarthropathies in circumpolar populations: II. Characterization of the populations.

For epidemiologic studies of spondyloarthropathy in circumpolar peoples of Chukotka, Russia and Alaska, we gathered demographic, physical and laboratory data to provide a background for evaluating and comparing factors that may influence susceptibility and clinical expression of disease. The study groups included the Chukchi and Siberian Eskimo of Russia and the Inupiat and Yupik Eskimo of Alaska. The 4 groups were remarkably similar in population structure, educational attainment, mean hemoglobin concentrations and frequency of the Class I histocompatibility antigen HLAB27. The Alaskan and Chukotkan groups were similar in mean height, but the Alaskans had higher body weights and significantly greater body mass indexes, probably a reflection of a shift away from traditional lifestyle and diet. Differences in the frequencies of ABO and MN blood group antigens were also apparent, with higher frequencies of blood group M in the Alaskan populations, particularly the Inupiat.

Spondyloarthropathies in circumpolar populations: I. Design and methods of United States and Russian studies.

Parallel epidemiologic studies of spondyloarthropathy in aboriginal circumpolar populations were carried out by U.S. and Russian investigators. These complementary studies used the same data collection instrument and disease criteria to facilitate comparisons. During three expeditions to Siberia, Russian investigators collected cross-sectional data from four settlements of Eskimos and Chukchi Indians on the Chukotka peninsula for a study of disease prevalence. U.S. researchers collected cross-sectional data from Eskimos in four Alaskan regions for studies of prevalence and longitudinal data for studies of clinical manifestations, natural history, disease impact, and health care utilization. The aims of these studies were to describe the spectrum of spondyloarthropathy in these populations, and to lay the groundwork for investigations of the role of specific genetic and environmental factors in the pathogenesis and expression of disease. These studies were carried out with a minimum disruption to the native people.

Arthritis and other rheumatic conditions: who is affected now, who will be affected later? National Arthritis Data Workgroup.

OBJECTIVE: We present national and state estimates for 1990 and projections for the year 2020 of the prevalence of self-reported arthritis and other rheumatic diseases and related activity limitations. We further suggest a research and policy agenda to address this important and growing public health problem. METHODS: Estimates and projections were derived from household interviews conducted for the 1989-1991 National Health Interview Survey, and were applied to United States census population estimates for 1990 and projections for 2020. RESULTS: The prevalence rate of self-reported arthritis and other rheumatic conditions in the United States is projected to increase from 15.0% (37.9 million) of the 1990 population to 18.2% (59.4 million) of the estimated 2020 population. Activity limitation attributed to these conditions is projected to increase from 2.8% (7.0 million) of the 1990 population to 3.6% (11.6 million) of the 2020 population. Prevalence rates were higher for older persons, women, residents of nonmetropolitan areas, and those with less education or lower income. CONCLUSIONS: Arthritis and other rheumatic conditions are frequent and disabling public health problems now, and are projected to become even more so by 2020. Implementing the suggested research and public health agenda could reduce the occurrence and impact of these conditions.

Discrepancies between patient recall and the medical record. Potential impact on diagnosis and clinical assessment of chronic disease.

BACKGROUND: During a case-control study, data necessary for fulfilling diagnostic and classification criteria for spondyloarthropathy were collected from 121 patients. OBJECTIVE: To study the potential impact of differences between patient recall and the medical record on diagnosis and clinical characterization of spondyloarthropathy as a model of chronic disease. METHODS: The study was conducted among four Alaskan Eskimo populations served by the Alaska Native Health Service. Two sets of historical data were compiled for each subject, one acquired during the interview and the other derived from the medical record. Paired items from the interview and the medical record were analyzed to determine discrepancies and consequent effects on diagnosis, classification, and disease characterization. RESULTS: Significant differences were observed in the reporting of genitourinary or diarrheal illnesses preceding or associated with arthritis, the occurrence of eye inflammation in association with joint pain, the occurrence of joint pain and back pain together, and the age at onset of back pain all of which are important to the diagnosis and classification of spondyloarthropathy. In contrast, for information needed to establish the probable inflammatory nature of back pain, patient interview was more helpful than the medical records, which did not provide adequate details to differentiate inflammatory from mechanical back pain. CONCLUSIONS: Patient recall bias can substantially affect diagnosis and clinical assessment of chronic disease, as exemplified by spondyloarthropathy. Reliance on records alone, however, may lead to underestimation of features that require subjective appraisal by the patient.

Prevalence of spondyloarthropathies in Alaskan Eskimos.

OBJECTIVE: To estimate the prevalence of spondyloarthropathies (SpA) in 2 Alaskan Eskimo populations, using improved methodology for case ascertainment and new, more inclusive classification criteria. METHODS: Through existing rheumatic disease registries, health care providers and the Alaska Area Native Health Service (AANHS) computerized patient information system, we identified all native residents of the 2 study regions with a diagnosis of any inflammatory arthritis or problems characteristic of SpA, such as iritis or persistent back pain. Individuals with such diagnoses or problems were evaluated in clinic, according to a standardized protocol (interview, examination), and by medical record review, pelvic radiography and laboratory tests. Each case was evaluated according to standard diagnostic criteria for the individual disease entities and by the Amor and European Spondylarthropathy Study Group (ESSG) preliminary classification criteria for SpA. RESULTS: We identified 104 cases of SpA in the combined Eskimo populations, an overall prevalence of 2.5% in adults aged 20 and over. Both undifferentiated (USpA) and reactive SpA were more common than ankylosing spondylitis (AS). CONCLUSION: Using the new criteria and a more effective approach to case ascertainment we found the prevalence of SpA to be about twice that found in our earlier studies of adult Eskimo populations. The prevalence of SpA was very similar in men and women. Despite the known high prevalence (25-40%) of HLA-B27 in the study populations we did not find the prevalence of any form of SpA to be as strikingly high as that of AS (6-10%) for the Canadian Haida.

Determination of size distribution of fat globules in intravenous fat emulsions by photon correlation spectroscopy.

A photon correlation spectroscopy method has been developed to characterize the size distribution of fat globules in intravenous fat emulsions (IFE) in terms of mean diameter, standard deviation of the distribution, and percentage of large particles outside the distribution. Mean fat globule diameters of samples of all IFE products available in Canada were about 0.3 microns, similar to values reported in the literature. The methodology is sufficiently sensitive to detect the presence of 5% by weight of 2 microns polystyrene microspheres in an intravenous fat emulsion. The effect of changes in instrument settings and variables on the results has been evaluated.