Anti-C1q antibodies in systemic lupus erythematosus.

OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. RESULTS: Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8-4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7-5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2-5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9-6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5-5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3-4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8-38.4, p < 0.01). CONCLUSIONS: Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.

Antiphospholipid antibodies and the brain: a consensus report.

This report discusses the difference between antiphospholipid antibodies (aPL) as a predictor for first and recurrent ischemic stroke, whether or not concomitant systemic lupus erythematosus (SLE) increases aPL-associated risk, and the association of aPL with other neurological manifestations. The neurological manifestations covered in this report were selected because they are among the most common, including cognitive dysfunction, headache, multiple sclerosis and seizures/epilepsy. Recommendations are made regarding further research that is needed to clarify remaining uncertainties.

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies.

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

International consensus for a definition of disease flare in lupus.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies.

OBJECTIVES: To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE. METHODS: We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine. RESULTS: A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A 'core set' of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart. CONCLUSIONS: A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.

Antiphospholipid syndrome and the brain in pediatric and adult patients.

The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.

Oral Salmonella typhimurium vaccine expressing circumsporozoite protein protects against malaria.

Immunization with radiation-attenuated malaria sporozoites induces potent cellular immune responses, but the target antigens are unknown and have not previously been elicited by subunit vaccines prepared from the circumsporozoite (CS) protein. A method is described here for inducing protective cell-mediated immunity to sporozoites by immunization with attenuated Salmonella typhimurium transformed with the Plasmodium berghei CS gene. These transformants constitutively express CS antigens and, when used to immunize mice orally, colonize the liver, induce antigen-specific cell-mediated immunity, and protect mice against sporozoite challenge in the absence of antisporozoite antibodies. These data indicate that the CS protein contains T cell epitopes capable of inducing protective cell-mediated immunity, and emphasize the importance of proper antigen presentation in generating this response. Analogous, orally administered vaccines against human malaria might be feasible.

CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus.

OBJECTIVES: There is an enrichment of immune response genes that are subject to copy number variations (CNVs). However, there is limited understanding of their impact on susceptibility to human diseases. CC chemokine ligand 3 like-1 (CCL3L1) is a potent ligand for the HIV coreceptor, CC chemokine receptor 5 (CCR5), and we have demonstrated previously an association between CCL3L1-gene containing segmental duplications and polymorphisms in CCR5 and HIV/AIDS susceptibility. Here, we determined the association between these genetic variations and risk of developing systemic lupus erythaematosus (SLE), differential recruitment of CD3+ and CD68+ leukocytes to the kidney, clinical severity of SLE reflected by autoantibody titres and the risk of renal complications in SLE. METHODS: We genotyped 1084 subjects (469 cases of SLE and 615 matched controls with no autoimmune disease) from three geographically distinct cohorts for variations in CCL3L1 and CCR5. RESULTS: Deviation from the average copy number of CCL3L1 found in European populations increased the risk of SLE and modified the SLE-influencing effects of CCR5 haplotypes. The CCR5 human haplogroup (HH)E and CCR5-Delta32-bearing HHG*2 haplotypes were associated with an increased risk of developing SLE. An individual's CCL3L1-CCR5 genotype strongly predicted the overall risk of SLE, high autoantibody titres, and lupus nephritis as well as the differential recruitment of leukocytes in subjects with lupus nephritis. The CCR5 HHE/HHG*2 genotype was associated with the maximal risk of developing SLE. CONCLUSION: CCR5 haplotypes HHE and HHG*2 strongly influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. These findings implicate a key role of the CCL3L1-CCR5 axis in the pathogenesis of SLE.

Gait and balance of transfemoral amputees using passive mechanical and microprocessor-controlled prosthetic knees.

BACKGROUND: Microprocessor-controlled knee joints appeared on the market a decade ago. These joints are more sophisticated and more expensive than mechanical ones. The literature is contradictory regarding changes in gait and balance when using these sophisticated devices. METHODS: This study employed a crossover design to assess the comparative performance of a passive mechanical knee prosthesis compared to a microprocessor-controlled knee joint in 15 subjects with an above-knee amputation. Objective measurements of gait and balance were obtained. RESULTS: Subjects demonstrated significantly improved gait characteristics after receiving the microprocessor-controlled prosthetic knee joint (p<0.01). Improvements in gait were a transition from a hyperextended knee to a flexed knee during loading response which resulted in a change from an internal knee flexor moment to a knee extensor moment. The participants' balance also improved (p<0.01). All conditions of the Sensory Organization Test (SOT) demonstrated improvements in equilibrium score. The composite score also increased. CONCLUSIONS: Transfemoral amputees using a microprocessor-controlled knee have significant improvements in gait and balance.

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.

Calculation of dose coefficients for radionuclides produced in a spallation neutron source utilizing NUBASE and the evaluated nuclear structure data file databases.

Based on a mercury spallation neutron source target, the UNLV Transmutation Research Program has identified 72 radionuclides with a half-life greater than or equal to a minute as lacking an appropriate reference for a published dose coefficient according to existing radiation safety dose coefficient databases. A method was developed to compare the nuclear data presented in the ENSDF and NUBASE databases for these 72 radionuclides. Due to conflicting or lacking nuclear data in one or more of the databases, internal and external dose coefficient values have been calculated for only 14 radionuclides, which are not currently presented in Federal Guidance Reports Nos. 11, 12, and 13 or Publications 68 and 72 of the International Commission on Radiological Protection. Internal dose coefficient values are reported for inhalation and ingestion of 1 microm and 5 microm AMAD particulates along with the f1 values and absorption types for the adult worker. Internal dose coefficient values are also reported for inhalation and ingestion of 1 microm AMAD particulates as well as the f1 values and absorption types for members of the public. Additionally, external dose coefficient values for air submersion, exposure to contaminated ground surface, and exposure to soil contaminated to an infinite depth are also presented.

Quality assurance methods and procedures used to verify consistency in calculating dose coefficients.

The development of a spallation neutron source with a mercury target will lead to the production of rare radionuclides. The dose coefficients for many of these radionuclides have not yet been published. A collaboration of universities and national labs has taken on the task of calculating dose coefficients for the rare radionuclides using the software package DCAL. The working group developed a procedure for calculating dose coefficients and a quality assurance (QA) program to verify the calculations completed. The first portion of this QA program was to verify that each participating group could independently reproduce the dose coefficients for a known set of radionuclides. The second effort was to divide the group of rare radionuclides among the independent participants in a manner that assured that each radionuclide would be redundantly and independently calculated, and the results subsequently be submitted for publication in a separate manuscript. The final aspect of this program was to resolve any discrepancies arising among the participants as a group. The output of the various software programs for six QA radionuclides, 144Nd, 201Au, 50V, 61Co, 41Ar, and 38S were compared among all members of the working group. Initially, a few differences in outputs were identified. This exercise identified weaknesses in the procedure, which has since been revised. After the revisions, dose coefficients were calculated and compared to published dose coefficients with good agreement. The present efforts involve generating dose coefficients for the rare radionuclides anticipated to be produced from the spallation neutron source should a mercury target be employed.

beta(2)-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program.

BACKGROUND: It has been hypothesized that immunoreactivity to beta(2)-glycoprotein 1 (beta2GP1)-dependent anticardiolipin antibody (aCL), but not beta2GP1-independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI). METHODS: We performed a nested case-control study examining aCL as a risk factor for ischemic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured beta2GP1-dependent and beta2GP1-independent aCL and anti-beta2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI, and in a control group of 1360 men who remained free of both conditions. RESULTS: Only beta2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor-adjusted relative odds for men with a positive versus a negative beta2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years. CONCLUSIONS: These data suggest that aCL IgG, particularly the beta2GP1-dependent variety, is an important predictor of future stroke and MI in men.

Focal and/or lateralized polymorphic delta activity. Association with either 'normal' or 'nonfocal' computed tomographic scans.

Focal continuous polymorphic delta activity (PDA) is classically taught to be associated with destructive lesions of cerebral white matter. One hundred patients with focal or lateralized continuous PDA recorded by an electroencephalogram who also had computed tomographic (CT) scans of the head performed at approximately the same time were studied. Thirty-three percent had normal or "nonfocal" abnormalities on their CT scans. Most of these had a history of either seizures (51%) or transient cerebral ischemia/stroke (27%); however, a wide variety of causes were possible. This high percentage of patients with focal continuous PDA without corresponding CT scan lesions supports the concept that the electroencephalogram is a physiologic study that is complementary to anatomic imaging techniques.

Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection.

This report summarizes the results of neurologic and cerebrospinal fluid (CSF) study findings in over 400 of the 649 human immunodeficiency virus-infected US Air Force personnel, evaluated as of Dec 31, 1987. Eighty percent of these patients were entirely asymptomatic and immunologically normal, 13% had low T-helper lymphocyte counts and/or cutaneous anergy, and only 7% had opportunistic infection. Sixty-three percent of all patients had some CSF abnormality. Sixty percent of the asymptomatic group had at least one abnormal result, over 25% had three or four CSF abnormalities, and over 7% had five or six abnormal values. When patients with evidence of blood-brain barrier leak were excluded, significant differences were seen between disease groups with regard to CSF glucose, CSF IgG levels, and CSF IgG synthesis. No human immunodeficiency virus-related central nervous system abnormalities were found on neurologic examination in immunologically intact asymptomatic patients regardless of CSF findings. No clear-cut predictor of impending central nervous system complications has, as yet, been identified from the CSF parameters studied.

Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals.

Although individuals with acquired immunodeficiency syndrome (AIDS) are often impaired on a variety of neuropsychological tasks, questions remain as to when neuropsychological decline can be reliably detected during the course of human immunodeficiency virus (HIV) infection. Detailed neuropsychological testing was accomplished on a cohort of 83 immunologically and neurologically intact asymptomatic HIV-infected individuals drawn from a larger pool of 649 US Air Force personnel with HIV antibodies. These asymptomatic subjects were compared with a group of HIV-negative subjects, and no significant differences in neuropsychological functioning were found. No significant neuropsychological differences were found as a function of cerebrospinal fluid abnormalities in these asymptomatic subjects. When data from 13 subjects with immune compromise were included in the analyses, those with abnormal cerebrospinal fluid values performed significantly poorer on a task of verbal memory, suggesting that cognitive dysfunction is antedated by immunological decline. Methodological problems that inhibit specification of the incidence, prevalence, and natural history of HIV-related cognitive impairment are discussed, as are data suggesting that previously published high estimates of the frequency of HIV-related dementia may not be representative of all HIV-infected populations.

Cerebrospinal fluid anti-cardiolipin antibodies in patients with HIV-1 infection.

Both cerebrospinal fluid (CSF) immunologic abnormalities and serum anti-cardiolipin antibodies (aCL) have been reported in patients with HIV-1 infection. The antibody specificity of only a small amount of the total CSF IgG in these patients is known, and is directed against a variety of HIV-1 antigens. The specificity of the remaining CSF IgG is unknown. We report the results of the first study of CSF aCL in an HIV-1-infected population. We measured aCL IgG and IgM in the CSF of 21 HIV-1-infected patients without nervous system symptoms or AIDS, and in four HIV-1-negative controls. Twelve HIV-1-infected patients had an abnormal serum aCL value and CSF immunologic abnormalities and 9 HIV-1-infected patients had either abnormal serum aCL or CSF immunologic abnormalities but not both, or were normal in both regards. There was no difference between any HIV-1-infected patient and controls for CSF aCL IgM. Nine of 12 patients with an abnormal serum aCL and CSF immunologic abnormalities had CSF aCL IgG values that were at least 5 SD above normal control values, whereas none of the remaining patients had abnormal CSF aCL IgG values. All patients with abnormal CSF aCL IgG values had an intact blood-brain barrier as evidenced by an albumin index of less than 9, and all had nonreactive CSF VDRL tests. These data demonstrate that aCL IgG is produced intrathecally in some HIV-1-infected patients.

CSF changes in a longitudinal study of 124 neurologically normal HIV-1-infected U.S. Air Force personnel.

Over a 2 year period, 124 neurologically normal HIV-1-infected patients had three successive cerebrospinal fluid (CSF) examinations approximately 1 year apart. Immunological status as measured by absolute CD4 counts in the blood identified two groups of patients over time: (a) a group with progressive CD4 decline (66 patients), and (b) a group with stable CD4 counts (58 patients). These two study groups provided us the opportunity to compare CSF changes (cells, protein, albumin index, IgG, IgG index, and IgG synthesis rate) in neurologically normal individuals with respect to immunological status over time. We found significantly increased intrathecal cellular response and IgG production over time independent of CD4 group. We conclude that any clinical study comparing CSF findings in neurologically symptomatic HIV-infected individuals must recognize and control for these CSF changes in neurologically asymptomatic patients.

Lack of cerebrospinal fluid myelin basic protein in HIV-infected asymptomatic individuals with intrathecal synthesis of IgG.

We evaluated 130 consecutive HIV-infected neurologically asymptomatic individuals for intrathecal IgG production and myelin basic protein (MBP) levels. Although 56.7% of immunologically normal and 68.8% of immunocompromised patients had some CSF abnormality, no patient had an abnormal MBP level. The lack of MBP elevation in the CSF of these patients suggests that the production of intrathecal IgG is not related to active demyelination.

Antiphospholipid antibodies and cerebral ischemia in young people.

The importance of a prothrombotic state as a cause of ischemic stroke in young adults is ill defined. We examined 46 unselected patients under age 50 years with cerebral ischemia for anticardiolipin antibody (aCL) and lupus anticoagulants (LA), over a 3-year-period. Age- and sex-matched patients with other neurologic diseases served as a noncerebral ischemia comparison group to test whether (1) stroke/transient ischemic attacks (TIA) in young people is associated with aCL and/or LA, and (2) their presence is specific to cerebral ischemia. In the stroke/TIA group, 21 patients had aCL or LA and 25 had neither, whereas in the control group, 2 patients had aCL and 24 had neither. Equal numbers of stroke/TIA patients with and without antiphospholipid antibodies (aPL) had other stroke risk factors. Patients with aPL and cerebral ischemia, however, had a more frequent history of multiple events than those without them. These antibodies occur with undue frequency in young patients with stroke/TIA and are not associated with a concurrent diagnosis of systemic lupus in most cases. A coexistent aPL-associated prothrombotic state may be a key determinant of whether patients with atherosclerosis, mitral valve prolapse, or other structural lesions experience recurrent ischemia.