Anti-Lipoprotein Lipase Antibodies in Patients with Hypertriglyceridemia without Associated Autoimmune Disease

Background: Anti-lipoprotein lipase antibodies have been described in rare cases of patients with hypertriglyceridemia. However, no systematic study evaluating these antibodies in patients with this lipid abnormality has been undertaken. Objectives: To analyze the correlation of anti-lipoprotein lipase (anti-LPL) antibodies with other laboratory findings in patients with hypertriglyceridemia but no autoimmune disease. Methods: We evaluated 44 hypertriglyceridemic patients without autoimmune disease. Clinical and laboratory evaluations included analyses of comorbidities, fasting lipid profile and anti-LPL antibodies. Results: Mean patient age was 55 +/- 10 years; 46% of the patients were female and 64% were Caucasian. The mean disease duration was 94.4 months and mean body mass index 28.7 +/- 3.6 kg/m(2); 34.0% were diabetic, 25.0% were obese, 72.7% had systemic arterial hypertension, 75% were sedentary, 15.9% were smokers, 56.8% had a family history of dyslipidemia, 45.5% had a family history of coronary insufficiency, 20.5% had acute myocardial infarction, 9.0% had undergone revascularization and 11.0% angioplasty, 79.5% were being treated with statins and 43.2% were taking fibrates. Median triglyceride levels were 254 mg/dl (range 100-3781 mg/dl), and total cholesterol level was 233 +/- 111 mg/dl. High-density lipoprotein was 42.6 +/- 15.4 mg/dl, low-density lipoprotein 110.7 +/- 42.4 mg/dl and very low-density lipoprotein 48 +/- 15 mg/dl. Anti-LPL antibodies were identified in 2 patients (4.5%), both of whom had a family history of dyslipidemia, coronary insufficiency and acute myocardial infarction; one had undergone myocardial revascularization and percutaneous transluminal coronary angioplasty, and both were using fibrates and had normal triglyceride levels. Conclusions: Our findings demonstrate a correlation between the immune response and dyslipoproteinemia in hypertriglyceridemic patients, suggesting that autoimmune disease contributes to the dyslipidemia process.

Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases

Background Despite the WHO recommendation that the 2010-2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population. Methods 1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behcet`s disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjogren`s syndrome, Takayasu`s arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener`s) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated. Results After immunisation, seroprotection rates (68.5% vs 82.9% p < 0.0001), seroconversion rates (63.4% vs 76.9%, p < 0.001) and the factor increase in GMT (8.9 vs 13.2 p < 0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p < 0.0001), RA (p < 0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p < 0.0001), RA (p < 0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p < 0.0001), RA (p < 0.0001) and PsA (p < 0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported. Conclusions The novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety. (ClinicalTrials.gov #NCT01151644)

KISS1R Intracellular Trafficking and Degradation: Effect of the Arg386Pro Disease-Associated Mutation

The goal of this study was to investigate how the Arg386Pro mutation prolongs KiSS-1 receptor (KISS1R) responsiveness to kisspeptin, contributing to human central precocious puberty. Confocal imaging showed colocalization of wild-type (WT) KISS1R with a membrane marker, which persisted for up to 5 h of stimulation. Conversely, no colocalization with a lysosome marker was detected. Also, overnight treatment with a lysosome inhibitor did not affect WT KISS1R protein, whereas overnight treatment with a proteasome inhibitor increased protein levels by 24-fold. WT and Arg386Pro KISS1R showed time-dependent internalization upon stimulation. However, both receptors were recycled back to the membrane. The Arg386Pro mutation did not affect the relative distribution of KISS1R in membrane and internalized fractions when compared to WT KISS1R for up to 120 min of stimulation, demonstrating that this mutation does not affect KISS1R trafficking rate. Nonetheless, total Arg386Pro KISS1R was substantially increased compared with WT after 120 min of kisspeptin stimulation. This net increase was eliminated by blockade of detection of recycled receptors, demonstrating that recycled receptors account for the increased responsiveness of this mutant to kisspeptin. We therefore conclude the following: 1) WT KISS1R is degraded by proteasomes rather than lysosomes; 2) WT and Arg386Pro KISS1R are internalized upon stimulation, but most of the internalized receptors are recycled back to the membrane rather than degraded; 3) the Arg386Pro mutation does not affect the rate of KISS1R trafficking-instead, it prolongs responsiveness to kisspeptin by decreasing KISS1R degradation, resulting in the net increase on mutant receptor recycled back to the plasma membrane.(Endocrinology 152: 1616-1626,2011)

Anti-Group A Streptococcal Vaccine Epitope STRUCTURE, STABILITY, AND ITS ABILITY TO INTERACT WITH HLA CLASS II MOLECULES

Streptococcus pyogenes infections remain a health problem in several countries due to poststreptococcal sequelae. We developed a vaccine epitope (StreptInCor) composed of 55 amino acids residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. The nuclear magnetic resonance (NMR) structure of the StreptInCor peptide showed that the structure was composed of two microdomains linked by an 18-residue alpha-helix. A chemical stability study of the StreptInCor folding/unfolding process using far-UV circular dichroism showed that the structure was chemically stable with respect to pH and the concentration of urea. The T cell epitope is located in the first microdomain and encompasses 11 out of the 18 alpha-helix residues, whereas the B cell epitope is in the second microdomain and showed no alpha-helical structure. The prediction of StreptInCor epitope binding to different HLA class II molecules was evaluated based on an analysis of the 55 residues and the theoretical possibilities for the processed peptides to fit into the P1, P4, P6, and P9 pockets in the groove of several HLA class II molecules. We observed 7 potential sites along the amino acid sequence of StreptInCor that were capable of recognizing HLA class II molecules (DRB1*, DRB3*, DRB4*, and DRB5*). StreptInCoroverlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules and could be considered as a universal vaccine epitope.

Cardiovascular risk factors associated with migraine among the elderly with a low income: The Sao Paulo Ageing & Health Study (SPAH)

Background: To investigate the association between cardiovascular risk-factor profile and migraine in the elderly, we evaluated a population sample of ageing men and women (65 years or more) living in a low-income area in the city of Sao Paulo, Brazil. Patients and Methods: We investigated migraine status and cardiovascular profile from a baseline of 1450 participants (65-102 years of age) of the Sao Paulo Ageing & Health Study (SPAH), a longitudinal population-based study with low-income elderly in Brazil. The following age and sex-adjusted cardiovascular risk factors were analyzed: blood pressure, pulse pressure, serum total and high-density lipoprotein cholesterol, body mass index, smoking, history of hypertension, diabetes and the 10-year risk of myocardial infarction or coronary heart disease death based on the Framingham Risk Score. Results: The overall prevalence of migraine was 11.4%, and it was 3 times more frequent among women than men (15.3% vs 5.4%; P < 0.0001). Migraineurs were younger than non-migraineurs (mean age 70.6 years vs 72.1 years; P = 0.001, respectively). There was no statistically significant difference regarding the cardiovascular risk-factor profile after adjustment for age and sex among migraineurs and non-migraineurs. Only a decrease in the risk of hypertension among women (OR 0.58; 95% CI 0.38-0.90; P = 0.01) was also observed even after adjustment for age. Conclusions: Overall, we did not find a worse cardiovascular risk profile among elderly migraineurs. An inverse association between hypertension and migraine in women warrants further investigation.

Collapsing glomerulopathy associated with proliferative lupus nephritis: reversible acute kidney injury

Collapsing glomerulopathy is a rare form of glomerular injury, characterized by segmental or global collapse of the glomerular capillaries, wrinkling and retraction of the glomerular basement membrane, and marked hypertrophy and hyperplasia of podocytes. Prognosis is usually poor, with most cases developing end-stage renal disease, in spite of treatment. The association of collapsing glomerulopathy and systemic lupus erythematosus is very unusual. In this report, we describe the first case of a simultaneous diagnosis of collapsing glomerulopathy and diffuse proliferative lupus nephritis. The case presented with acute kidney injury and nephrotic syndrome and evolved with partial remission of nephrotic syndrome and recovery of renal function after aggressive treatment with intravenous cyclophosphamide and methylprednisolone. Lupus (2011) 20, 98-101.

High sucrose intake in rats is associated with increased ACE2 and angiotensin-(1-7) levels in the adipose tissue

Sucrose-fed rats, a model of metabolic syndrome, are characterized by insulin resistance, obesity, hypertension, and high plasma levels of triacylglycerols and angiotensin II (Ang II). However, whether tissue renin-angiotensin system (RAS) is altered in metabolic syndrome is unclear. To study this issue, food ad libitum and water (C) or 20% sucrose solution (SC) were given to adult male Wistar rats, for 30 days. Body weight (BW), blood pressure (BP), epididymal adipose tissue (EPI) mass, rate of in vivo fatty acid (FA) synthesis in EPI, circulating glucose, insulin, leptin, angiotensins I and II, triacylglycerols, and plasma renin (PRA) and angiotensin-converting enzyme (ACE) activities were evaluated. In kidneys and EPI, gene and protein expression of type 1 (AT(1)) and 2 (AT(2)) Ang II receptors, ACE, angiotensinogen (ACT) as well as protein expression of angiotensin-converting enzyme 2 (ACE2) were determined. In both tissues, Ang I, Ang II and Ang-(1-7) contents were also measured by HPLC. In SC rats higher BP, EPI mass, circulating triacylglycerols, insulin, leptin, PRA and, Ang II were found. In EPI, the rate of in vivo FA synthesis was associated with increased Ang-(1-7), protein expression of AT(1) and AT(2) receptors, ACE2, ACT, and gene expression of ACT although a reduction in ACE activity and in adipose Ang I and Ang II contents was observed. In kidneys, AT(1) and AT(2), ACE and ACT gene and protein expression as well as protein expression of ACE2 were unaltered while Ang II, Ang-(1-7) and ACE activity increased. These RAS component changes seem to be tissue specific and possibly are related to enhancement of FA synthesis, EPI mass and hypertension. (C) 2010 Elsevier B.V. All rights reserved.

Myelin proteolipid protein expressed in COS-1 cells is targeted to actin-associated surfaces

The compact myelin sheath represents one of the largest expanses of membrane-membrane contact in the body and, in the central nervous system, requires the myelin proteolipid protein (PLP) for assembly, To determine whether the molecular properties of PLP promote membrane adhesion and direct its subcellular localization in the absence of oligodendrocyte-specific targeting mechanisms, PLP was expressed in COS-I fibroblasts, Immunofluorescence staining indicated that PUP was translated effectively, transited the rough endoplasmic reticulum and Golgi apparatus, was delivered to the cell surface, and was endocytosed, In the plasma membrane, the PLP distribution was patchy and only sporadically coincided with sites of membrane-membrane contact between PLP-expressing cells, PLP was not randomly distributed, however, but correlated closely with microfilament locations in leading edge membranes and microvilli, as demonstrated by phalloidin double labeling, Our results indicate that even in non-myelinating cells, PLP can be concentrated in membranes associated with movement and growth, and suggest possible roles for the actin cytoskeleton in PLP localization, As PLP, DM20, and the DM20-like M6 protein all associate with actin-enriched membranes, this may be a common feature of PLP/DM20 gene family members. (C) 1997 Wiley-Liss, Inc.

Interleukin-1 receptor antagonist gene (IL1RN) polymorphism possibly associated to severity of rheumatic carditis in a Brazilian cohort

Aims: To evaluate the IL1RN polymorphism as a possible marker for Rheumatic Fever (RF) susceptibility or disease severity. Methods: The genotypes of 84 RF patients (Jones criteria) and 84 normal race-matched controls were determined through the analysis of the number of 86-bp tandem repeats in the second intron of IL1RN. The DNA was extracted from peripheral-blood leukocytes and amplified with specific primers. Clinical manifestations of RF were obtained through a standardized questionnaire and an extensive chart review. Carditis was defined as new onset cardiac murmur that was perceived by a trained physician with corresponding valvae regurgitation or stenosis on echocardiogram. Carditis was classified as severe in the presence of congestive heart failure or upon the indication for cardiac surgery. The statistical association among the genotypes, RF and its clinical variations was determined. Results: The presence of allele I and the genotype A1/A1 were found less frequently among patients with severe carditis when compared to patients without this manifestation (OR = 0.11, p = 0.031; OR = 0.092, p = 0.017). Neither allele I nor allele 2 were associated with the presence of RF (p = 0.188 and p = 0.106), overall carditis (p = 0.578 and p = 0.767), polyarthritis (p = 0.343 and p = 0.313) and chorea (p = 0.654 and p = 0.633). Conclusion: In the Brazilian population, the polymorphism of the IL-1ra gene is a relevant factor for rheumatic heart disease severity. (C) 2009 Elsevier Ltd. All rights reserved.

Tuberculosis-Associated Collapsing Glomerulopathy: Remission after Treatment

Collapsing glomerulopathy (CG) is a severe form of nephrotic syndrome and has been mostly associated with human immunodeficiency virus (HIV) infection. Treatment response is poor, and the disease frequently leads to end-stage renal disease. More recently, CG has been described in association with other conditions, such as drug exposure and other infections, but renal prognosis remains unfavorable. This paper reports an interesting case of an HIV-negative patient with tuberculosis-related CG who needed dialysis for five months but presented full renal recovery after tuberculosis (TB) treatment and corticotherapy.

Anisotropic correlated electron model associated with the Temperley-Lieb algebra

We present an anisotropic correlated electron model on a periodic lattice, constructed from an R-matrix associated with the Temperley-Lieb algebra. By modification of the coupling of the first and last sites we obtain a model with quantum algebra invariance.

Air pollution and antibodies against modified lipoproteins are associated with atherosclerosis and vascular remodeling in hyperlipemic mice

We analyzed the impact of chronic exposure to urban air pollution on the development of atherosclerosis. Hyperlipemic mice (LDLR(-/-)) were submitted to a high fat diet and air pollution for four months. We measured the susceptibility of LDL to oxidative modifications (TBARS), the presence of anti-oxLDL and an apoB-derived peptide (apoB-D) in blood and the degree of atherosclerosis in the aortic arch. Air pollution increased the susceptibility of LDL to oxidation as well as anti-oxLDL and anti-apo-B levels. These levels were even higher than in mice submitted to a high fat diet and non-polluted air. The lipid content of the atherosclerotic plaques in the aorta was increased in groups with a high cholesterol diet independently of the air quality. However, the thickness of the arterial wall was greater in mice fed a high lipid diet with polluted air. Thus, we conclude that urban air pollution exacerbates the susceptibility of LDL to oxidation, atherogenesis and vascular remodeling in hyperlipemic mice and that an immune response accompanies this process. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection

HLA-G is a non-classic Human Leukocyte Antigen (HLA-G) Class I of low polymorphism and restricted tissue distribution that displays tolerogenic functions. In heart transplantation and in combined liver/renal allograft transplantation, the expression of HLA-G has been associated with a lower incidence of acute graft rejection episodes and absence of chronic dysfunction. Since the expression of HLA-G in renal biopsies has been investigated only in few patients who received a combined kidney and liver transplant, in this study we performed a cross-sectional study, systematically comparing the expression of HLA-G in post-transplanted renal grafts, stratifying patients according to the presence or absence of rejection. Patients and Methods: Seventy-three renal specimens (10 with acute rejection and 13 with chronic allograft nephropathy, and 50 with no signs of rejection) were immunohistochemically evaluated for HLA-G expression. Results: In the group as a whole, HLA-G molecules were detected in 40 cases (54.8%). Among specimens that presented HLA-G expression, 2 out of 40 (5%) exhibited acute rejection, 2 (5%) exhibited chronic allograft nephropathy, and the remaining 36 (90%) exhibited no signs of rejection. The comparison between patients with rejection and those without rejection showed that the expression of HLA-G was significantly increased in specimens exhibiting no signs of rejection (p<0.0001). Considering only patients with acute rejection, 8 out of 10 patients showed no HLA-G expression in their kidney biopsies when compared to patients exhibiting no signs of rejection and absence of HLA-G was observed in 14 out of 50 (p=0.0032). Similarly, considering only patients with chronic allograft nephropathy, absence of HLA-G expression was observed in I I out of 13 specimens, whereas in patients without rejection absence of HLA-G was observed in 14 out of 50 (p=0.003). Therapy with tacrolimus was significantly associated with the expression of HLA-G and a better graft prognosis. Conclusions: Our results suggest that HLA-G expression in the kidney allograft and the use of tacrolimus are associated with a lower frequency of acute renal rejection and chronic allograft nephropathy. (c) 2007 Elsevier B.V. All rights reserved.

Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era

Background-Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results-Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n = 190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. Conclusions-In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation. (Circulation. 2010; 122: 156-163.)

Reciprocal interactions of obstructive sleep apnea and hypertension associated with ACE I/D polymorphism in males

Background: The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism gene contributes to the genesis of hypertension (HTN) and may help explain the relationship between obstructive sleep apnea (OSA) and HTN. However, ACE is a pleiotropic gene that has several influences, including skeletal muscle and control of ventilation. We therefore tested the hypothesis that ACE polymorphism influences OSA severity. Methods: Male OSA patients (apnea-hypopnea index [AHI] > 5 events/h) from 2 university sleep centers were evaluated by polysomnography and ACE I/D polymorphism genotyping. Results: We studied 266 males with OSA (age = 48 +/- 13y, body mass index = 29 5kg/m(2), AHI = 34 +/- 25events/h). HTN was present in 114 patients (43%) who were older (p < 0.01), heavier (p < 0.05) and had more severe OSA (p < 0.01). The I allele was associated with HTN in patients with mild to moderate OSA (p < 0.01), but not in those with severe OSA. ACE I/D polymorphism was not associated with apnea severity among normotensive patients. In contrast. the only variables independently associated with OSA severity among patients with hypertension in multivariate analysis were BMI (OR = 1.12) and 11 genotype (OR = 0.27). Conclusions: Our results indicate reciprocal interactions between OSA and HTN with ACE I/D polymorphism, suggesting that among hypertensive OSA males, the homozygous ACE I allele protects from severe OSA. (C) 2009 Elsevier B.V. All rights reserved.