Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus

OBJECTIVE: To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels. METHODS: The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set. RESULTS: We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives. CONCLUSION: Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.     

Suppressor of cytokine signaling-3 Provides a novel interface in the cross-talk between angiotensin II and insulin signaling systems

Angiotensin II inhibits insulin-induced activation of phosphatidylinositol 3-kinase through a mechanism, at least in part, dependent on serine phosphorylation of the insulin receptor and insulin receptor substrates (IRS)-1/2. Recent evidence shows that suppressor of cytokine signaling-3 (SOCS-3) is induced by insulin and angiotensin II and participates in the negative control of further stimulation of each of these signaling systems independently. In the present study, we evaluated the interaction of angiotensin II-induced SOCS-3 with the insulin signaling pathway in the heart of living rats. A single iv dose of angiotensin II promotes a significant increase of SOCS-3 in heart, an effect that lasts up to 180 min. Once induced, SOCS-3 interacts with the insulin receptor, JAK-2, IRS-1, and IRS-2. The inhibition of SOCS-3 expression by a phosphorthioate-modified antisense oligonucleotide partially restores angiotensin II-induced inhibition of insulin-induced insulin receptor, IRS-1 and IRS-2 tyrosine phosphorylation, and IRS-1 and IRS-2 association with p85-phosphatidylinositol 3-kinase and [Ser473] phosphorylation of Akt. Moreover, the inhibition of SOCS-3 expression partially reverses angiotensin II-induced inhibition of insulin-stimulated glucose transporter-4 translocation to the cell membrane. These results are reproduced in isolated cardiomyocytes. Thus, SOCS-3 participates, as a late event, in the negative cross-talk between angiotensin II and insulin, producing an inhibitory effect on insulin-induced glucose transporter-4 translocation.     

The patterns of use and factors associated with the patient admission of hospital emergencies for asthma and chronic obstructive pulmonary disease

The aim of this study was to describe the epidemiological characteristics of emergencies caused by asthma and chronic obstructive pulmonary disease (COPD) at the Hospital Clínico Universitario of Valencia (Spain) and to analyze factors related to hospital admissions for the same causes. Emergency room medical records for 1993 to 1995 of patients older than 14 years of age were examined to identify those due to asthma or COPD, according to established protocol. Demographic variables were described, followed by Poisson regression analysis of time and seasonal factors affecting emergencies. Factors related to hospital admission were analyzed by logistic regression, taking into account age group, sex, place of residence, and the year, month, day and hour of emergency room arrival. Asthma patients amounted to 1% of emergencies, while COPD patients accounted for 2%. The admission rate for women with asthma was higher than for men (F/M ratio = 0.78), whereas the rate for men with COPD was higher than for women (F/M ratio = 3.14). The largest age groups with asthma emergencies included young people aged 15 to 24 years old and those over 60. Hospital admissions or transfers to other hospitals were ordered for 17.4% of asthma patients and 38.8% of COPD patients. Nearly a third of COPD patients and a fifth of asthma patients were readmitted within the ten days following the first emergency. Clear temporal patterns of COPD emergency were observed for month (most occurring in winter), day of the week (most on Monday) and hour of the day (most during daytime hours, with fewer at midday). The time patterns were less evident for asthma emergencies, although the likelihood of admission because of asthma varied by month and day of the week. Emergency room records may be useful for studying the patterns of respiratory disease presentation. Other possible uses are epidemiologic monitoring and evaluation of health care quality.     

An effective strategy for diagnosing occupational asthma: use of induced sputum

Monitoring airway inflammation by means of induced sputum cell counts seems to improve the management of asthma. We sought to assess whether such monitoring at the end of periods at and away from work combined with the monitoring of PEF could improve the diagnosis of occupational asthma. We enrolled subjects suspected of having occupational asthma. Serial monitoring of PEF was performed during 2 weeks at and away from work. At the end of each period, induced sputum was collected. Specific inhalation challenge was subsequently performed. PEF graphs were interpreted visually by five independent observers. Forty-nine subjects, including 23 with positive specific inhalation challenge, completed the study. The addition of sputum cell counts to the monitoring of PEF increased the specificity of this test, respectively, by 18 (range [r] 13.7-25.5) or 26.8% (r 24.8-30.4) depending if an increase of sputum eosinophils greater than 1 or 2% when at work was considered as significant. The sensitivity increased by 8.2% (r 4.1-13.4) or decreased by 12.3% (r 3.1-24.1) depending on the cutoff value in sputum eosinophils chosen (greater than 1 or 2%, respectively). The addition of sputum cell counts to PEF monitoring is useful to improve the diagnosis of occupational asthma.     

Blood fluidity is related to the ability to oxidize lipids at exercise

We previously reported in rugbywomen correlations between RBC deformability and the ability to oxidize at exercise more lipids. This surprising finding might of course be spurious, or reflect the importance of the balance of substrates at exercise on baseline parameters that regulate blood rheology. Actually, the capacity of skeletal muscle to utilize either lipid or carbohydrate as fuels strongly influences whole body metabolism both at rest and during exercise. While the healthy skeletal muscle has substantial metabolic flexibility and is able to switch from predominantly lipid o oxidation during fasting or endurance exercise to increased glucose oxidation in conditions of insulin stimulation, obese individuals and those with type 2 diabetes manifest higher lipid oxidation during insulin-stimulated conditions despite lower rates of lipid oxidation during fasting or prolonged exercise. A low ability to oxidize and to periodically deplete triglyceride in muscle is associated with raised blood lipids. In addition, high carbohydrate oxidation rates in the mitochondrion are likely to promote more free radical generation. An increase in either blood lipids or free radicals is likely to induce profound hemorheological effects. We present here hemorheological studies in various populations with the use of exercise calorimetry in order to assess this switch of substrates. These studies further evidence negative correlations between the ability to oxidize lipids at exercise and parameters of blood viscosity. Correlations found between RBC deformability and the ability to oxidize at exercise more lipids may be due to effects of endurance training on lipid oxidation which may in turn modify both lipid metabolism and free radical generation, thus influencing RBC rheology.