Anti‐LG3 Antibodies Aggravate Renal Ischemia–Reperfusion Injury and Long‐Term Renal Allograft Dysfunction

Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia–reperfusion injury (IRI) can modify self‐antigenic targets. We hypothesized that ischemia–reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti‐LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti‐LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti‐AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti‐LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti‐LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti‐LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long‐term outcomes.     

A comprehensive view of sex-specific issues related to cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality in women. In fact, CVD is responsible for a third of all deaths of women worldwide and half of all deaths of women over 50 years of age in developing countries. The prevalence of CVD risk factor precursors is increasing in children. Retrospective analyses suggest that there are some clinically relevant differences between women and men in terms of prevalence, presentation, management and outcomes of the disease, but little is known about why CVD affects women and men differently. For instance, women with diabetes have a significantly higher CVD mortality rate than men with diabetes. Similarly, women with atrial fibrillation are at greater risk of stroke than men with atrial fibrillation. Historically, women have been underrepresented in clinical trials. The lack of good trial evidence concerning sex-specific outcomes has led to assumptions about CVD treatment in women, which in turn may have resulted in inadequate diagnoses and suboptimal management, greatly affecting outcomes. This knowledge gap may also explain why cardiovascular health in women is not improving as fast as that of men. Over the last decades, mortality rates in men have steadily declined, while those in women remained stable. It is also becoming increasingly evident that gender differences in cultural, behavioural, psychosocial and socioeconomic status are responsible, to various degrees, for the observed differences between women and men. However, the interaction between sex-and gender-related factors and CVD outcomes in women remains largely unknown.     

Outcomes in adults with bicuspid aortic valves

Nikolaos Tzemos, MD; Judith Therrien, MD; James Yip, MD; George Thanassoulis, MD; Sonia Tremblay, MD; Michal T. Jamorski, BSc; Gary D. Webb, MD; Samuel C. Siu, MD, SM

JAMA. 2008;300(11):1317-1325.

Context  Bicuspid aortic valve is the most common congenital cardiac anomaly in the adult population. Cardiac outcomes in a contemporary population of adults with bicuspid aortic valve have not been systematically determined.

Objective  To determine the frequency and predictors of cardiac outcomes in a large consecutive series of adults with bicuspid aortic valve.

Design, Setting, and Participants  Cohort study examining cardiac outcomes in 642 consecutive ambulatory adults (mean [SD] age, 35 [16] years; 68% male) with bicuspid aortic valve presenting to a Canadian congenital cardiac center from 1994 through 2001 and followed up for a mean (SD) period of 9 (5) years. Frequency and predictors of major cardiac events were determined by multivariate analysis. Mortality rate in the study group was compared with age- and sex-matched population estimates.

Main Outcome Measures  Mortality and cause of death were determined. Primary cardiac events were defined as the occurrence of any of the following complications: cardiac death, intervention on the aortic valve or ascending aorta, aortic dissection or aneurysm, or congestive heart failure requiring hospital admission during the follow-up period.

Results  During the follow-up period, there were 28 deaths (mean [SD], 4% [1%]). One or more primary cardiac events occurred in 161 patients (mean [SD], 25% [2%]), which included cardiac death in 17 patients (mean [SD], 3% [1%]), intervention on aortic valve or ascending aorta in 142 patients (mean [SD], 22% [2%]), aortic dissection or aneurysm in 11 patients (mean [SD], 2% [1%]), or congestive heart failure requiring hospital admission in 16 patients (mean [SD], 2% [1%]). Independent predictors of primary cardiac events were age older than 30 years (hazard ratio [HR], 3.01; 95% confidence interval [CI], 2.15-4.19; P<.001), moderate or severe aortic stenosis (HR, 5.67; 95% CI, 4.16-7.80; P<.001), and moderate or severe aortic regurgitation (HR, 2.68; 95% CI, 1.93-3.76; P<.001). The 10-year survival rate of the study group (mean [SD], 96% [1%]) was not significantly different from population estimates (mean [SD], 97% [1%]; P = .71). At last follow-up, 280 patients (mean [SD], 45% [2%]) had dilated aortic sinus and/or ascending aorta.

Conclusions  In this study population of young adults with bicuspid aortic valve, age, severity of aortic stenosis, and severity of aortic regurgitation were independently associated with primary cardiac events. Over the mean follow-up duration of 9 years, survival rates were not lower than for the general population.

     

Correlates of plasma very-low-density lipoprotein concentration and composition in premenopausal women

Potential correlates of plasma very-low-density lipoprotein (VLDL) concentration and composition were studied in a sample of 75 premenopausal women. Fasting plasma free fatty acid (FFA) levels, as well as plasma glucose and insulin levels in the fasting state and during an oral glucose tolerance test, displayed significant positive correlations with plasma triglyceride (TG) and VLDL-TG levels (P less than .005). Plasma post-heparin lipoprotein lipase (LPL) activity, measured in a subsample of 31 women from the original sample, was negatively correlated with plasma TG, VLDL-cholesterol (CHOL), VLDL-TG, and VLDL-apolipoprotein (apo) B concentrations (.005 greater than P less than .05). Multivariate analyses showed that, after LPL was considered, the insulin area was the only other metabolic variable studied that was significantly correlated with VLDL-apo B concentration, whereas fasting FFA levels were significantly correlated with plasma TG and VLDL-TG levels. ANOVA revealed that plasma VLDL-CHOL, VLDL-TG, and VLDL-apo B levels were not associated with the glucose area, but were significantly associated with the insulin area (P less than .005). When the effect of insulin area was controlled for, the plasma FFA levels did not contribute significantly to the variance in VLDL-CHOL and VLDL-apo B, but showed an independent effect on VLDL-TG levels (P less than .05). Finally, stepwise multiple regression analyses indicated that once the variance explained by plasma LPL activity and by the insulin area was considered, no other metabolic variable could account for the variation in VLDL-CHOL and VLDL-apo B levels, whereas fasting FFA levels explained a further 5% of the VLDL-TG variance and one third of the variance observed in the VLDL-TG/apo B ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical Prediction and Diagnosis of Neurosyphilis in HIV-Infected Patients with Early Syphilis

The diagnosis of neurosyphilis (NS) is a challenge, especially in HIV-infected patients, and the criteria for deciding when to perform a lumbar puncture (LP) in HIV-infected patients with syphilis are controversial. We retrospectively reviewed demographic, clinical, and laboratory data from 122 cases of HIV-infected patients with documented early syphilis who underwent an LP to rule out NS, and we evaluated 3 laboratory-developed validated real-time PCR assays, the Treponema pallidum particle agglutination (TPPA) assay, the fluorescent treponemal antibody absorption (FTA-ABS) assay, and the line immunoassay INNO-LIA Syphilis, for the diagnosis of NS from cerebrospinal fluid (CSF) samples of these patients. NS was defined by a reactive CSF-VDRL test result and/or a CSF white blood cell (WBC) count of >20 cells/μl. Thirty of the 122 patients (24.6%) had early NS. Headache, visual symptoms, a CD4 cell count of <500 cells/μl, and viremia, as defined by an HIV-1 RNA count of ≥50 copies/ml, were associated with NS in multivariate analysis (P = <0.001 for each factor). Blood serum rapid plasma reagin (RPR) titers were not associated with early NS (P = 0.575). For the diagnosis of NS, the PCR, FTA-ABS, TPPA, and INNO-LIA assays had sensitivities of 58%, 100%, 68%, and 100%, specificities of 67%, 12%, 49%, and 13%, and negative predictive values of 85%, 100%, 84%, and 100%, respectively. Visual disturbances, headache, uncontrolled HIV-1 viremia, and a CD4 cell count of <500 cells/μl were predictors of NS in HIV-infected patients with early syphilis, while blood serum RPR titers were not; therefore, RPR titers should not be used as the sole criterion for deciding whether to perform an LP in early syphilis. When applied to CSF samples, the INNO-LIA Syphilis assay easily helped rule out NS.     

Myopathy in a rhesus monkey with biopsy findings similar to human sporadic inclusion body myositis

A rhesus macaque with generalized muscle atrophy and musculotendinous contractures was detected in our research center. Muscle biopsies showed myofibers with rimmed vacuoles and eosinophilic hyaline inclusions, accumulations of CD8+ and CD4+ lymphocytes and expression of major histocompatibility complex class I in myofibers. Intracellular inclusions were positive to Congo red. Semithin sections and transmission electron microscopy showed autophagic vacuoles within myofibers and myonuclei with inclusions of filaments. These morphological observations conform with the diagnostic criteria of human sporadic inclusion body myositis. This is the first report of this myopathy in nonhuman primates.