Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity

Objective

Recent evidence suggests that anti‐Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti‐Ro/SSA–positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10–60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti‐Ro/SSA–associated QTc prolongation in adult patients with CTD is related to antibody level and specificity.

Methods

Forty‐nine adult patients with CTD underwent a resting 12‐lead electrocardiogram recording to measure QTc interval, and a venous withdrawal to determine anti‐Ro/SSA antibody level and specificity (anti–Ro/SSA 52 kd and anti–Ro/SSA 60 kd) by immunoenzymatic methods and Western blotting.

Results

In our population, a direct correlation was demonstrated between anti–Ro/SSA 52‐kd level and QTc duration (r = 0.38, P = 0.007), patients with a prolonged QTc had higher levels of anti–Ro/SSA 52 kd with respect to those with a normal QTc (P = 0.003), and patients with a moderate to high level (≥50 units/ml) of anti–Ro/SSA 52 kd showed a longer QTc interval (P = 0.008) and a higher QTc prolongation prevalence (P = 0.008) than those with a low positive/negative level (<50 units/ml). On the contrary, no association was found between QTc and anti–Ro/SSA 60‐kd level.

Conclusion

In anti‐Ro/SSA–positive adult patients with CTD, the occurrence of QTc prolongation seems strictly dependent on the anti–Ro/SSA 52‐kd level. This finding, possibly explaining the different QTc prolongation prevalence reported, strengthens the hypothesis that an extremely specific autoimmune cross‐reaction is responsible for the anti‐Ro/SSA–dependent interference on ventricular repolarization.     

The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project

Background

Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical use and efficacy of these two approaches in patients with high risk hematologic conditions.

Design and Methods

An electronic medical record system, the “Hema e-Chart”, was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy.

Results

Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P<0.001). The rate of deaths attributable to invasive fungal diseases was significantly lower in subjects treated with empirical antifungal therapy (1 case; 7.1%) than in subjects treated with pre-emptive therapy (11 cases; 22.5%) (P=0.002).

Conclusions

These data indicate that empirical antifungal treatment decreased the incidence of invasive fungal disease and of attributable mortality with respect to a pre-emptive antifungal approach in neutropenic febrile patients with hematologic malignancies. (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01069887","term_id":"NCT01069887"}}NCT01069887)     

Accessing the transport properties of graphene and its multilayers at high carrier density

We present a comparative study of high carrier density transport in mono-, bi-, and trilayer graphene using electric double-layer transistors to continuously tune the carrier density up to values exceeding 10(14) cm(-2). Whereas in monolayer the conductivity saturates, in bi- and trilayer filling of the higher-energy bands is observed to cause a nonmonotonic behavior of the conductivity and a large increase in the quantum capacitance. These systematic trends not only show how the intrinsic high-density transport properties of graphene can be accessed by field effect, but also demonstrate the robustness of ion-gated graphene, which is crucial for possible future applications.     

Dietary fat and gestational hyperglycaemia

Aims/hypothesis: The purpose of this study was to investigate the relation between life-style habits and glucose abnormalities in Caucasian women with and without conventional risk factors for gestational diabetes. Methods: A total of 126 pregnant women with gestational diabetes, 84 with impaired glucose tolerance and 294 with normal glucose tolerance, identified by sequential screening, were interviewed to determine their usual weekly food pattern, amount of exercise, smoking habits and alcohol intake. Results: Patients with glucose abnormalities were older and shorter in height and had significantly higher BMI before pregnancy, percentage of diabetic first-degree relatives and higher intake of saturated fat. Patients without known risk factors for gestational diabetes (i. e. younger than 35 years of age, BMI < 25 kg/m², no first-degree diabetic relatives) included 40 with impaired glucose tolerance or gestational diabetes. In a multiple logistic regression model age, short stature, familial diabetes, BMI and percentages of saturated fat were associated with impaired glucose tolerance or gestational diabetes in all patients, after adjustment for gestational age. In patients without conventional risk factors only percentages of saturated fat (OR = 2.0; 95 %-CI = 1.2–3.2) and polyunsaturated fat (OR = 0.85; 95 %-CI = 0.77–0.92) were associated with gestational hyperglycaemia, after adjustment for age, gestational age and BMI. Conclusion/interpretation: Saturated fat has an independent role in the development of gestational glucose abnormalities. This role is more important in the absence of conventional risk factors suggesting that glucose abnormalities could be prevented during pregnancy, at least in some groups of women. [Diabetologia (2001) 44: 972–978] Received: 16 January 2001 and in revised form: 23 April 2001     

Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura

The role of rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Patients were scheduled to receive intravenous rituximab at the dose of 375 mg/m(2) once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but were of modest intensity and did not require discontinuation of treatment. A complete response (platelet count greater than 100 x 10(9)/L) was observed in 5 cases, a partial response (platelet count between 50 and 100 x 10(9)/L) in 5 cases, and a minor response (platelet count below 50 x 10(9)/L, with no need for continued treatment) in 3 cases, with an overall response rate of 52%. In 7 cases, responses were sustained (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In patients with a complete or partial response, a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome, although there was a suggestion that women and younger patients have a better chance of response. In conclusion, rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted. (Blood. 2001;98:952-957)     

Induction of replication of Epstein-Barr virus DNA by 12-O-tetradecanoyl-phorbol-13-acetate. II. Inhibition by retinoic acid and 9-(2-hydroxyethoxymethyl) guanine

An Epstein-Barr virus (EBV)-producing cell line (P3HR-1) is readily inducible for EBV DNA replication by the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The effects of an antiherpesvirus drug, Acyclovir (ACV) [9-(2-hydroxyethoxymethyl)-guanine], and a tumor promoter antagonist, retinoic acid (RA), were tested on EBV DNA replication in P3HR-1 cells. The activation of P3HR-1 cells by TPA greatly stimulates [³H]thymidine incorporation into the viral DNA as determined by analysis on cesium chloride gradients. This effect is completely inhibited by RA. However, RA has no inhibitory effect on the spontaneously induced viral DNA replication that occurs in P3HR-1 cells not treated with TPA. In contrast, ACV inhibits both the spontaneously induced and TPA-induced EBV DNA replication. The discriminatory effect of ACV and RA on viral DNA replication in P3HR-1 cells is further demonstrated by cRNA-DNA hybridization with EBV-specific cRNA.     

Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort

OBJECTIVE: To evaluate the prevalence of prolonged QT interval and dispersion in a population-based cohort of type 2 diabetic patients and their relationship with clinical and metabolic variables. DESIGN: Cross-sectional population-based cohort. SETTING: Diabetes clinics and general practitioners in Casale Monferrato (Northern Italy). SUBJECTS: A total of 1357 patients with known type 2 diabetes (70% of the cohort). MAIN OUTCOMES MEASURES: Albumin excretion rate and coronary heart disease (CHD); a standard supine 12-lead electrocardiogram (ECG) was recorded and coded according to the Minnesota code criteria. QT interval corrected for heart rate (QTc) > 0.44 s and QTc dispersion > 0.080 s were considered abnormally prolonged. RESULTS: Prevalence of increased QTc duration and QTc dispersion were 25.8% (95% CI 23.5-28.3) and 33.1% (95% CI 30.6-35.7), with no sex differences. No metabolic differences were found, apart from fibrinogen and creatinine levels, which were higher in patients with increased QTc dispersion. Patients with CHD had higher mean adjusted values of QTc and QTc dispersion, whereas no association was found with albumin excretion rate (AER) and diabetes treatment. QTc duration and QTc dispersion were significantly correlated (0.17, P < 0.001). In multiple regression analysis, only CHD was independently associated with QTc, after adjustment for age and sex (beta=0.010, P < 0.001, R2=2.5%); as regards QTc dispersion, a similar association with CHD was found (beta=0.20, P < 0.001, R2=4.8%). CONCLUSIONS: This population-based study shows a considerably high prevalence of increased QTc and QTc dispersion in type 2 diabetic patients and their association with CHD. These findings have both epidemiological and clinical relevance, as they might be implicated in the excess mortality risk of type 2 diabetic patients.     

Increased serum resistin in adults with prader-willi syndrome is related to obesity and not to insulin resistance

CONTEXT: Determinants of insulin resistance in Prader-Willi syndrome (PWS) are not completely understood. The discovery of several adipokines with relevant effects on insulin resistance and cardiovascular complications of metabolic syndrome offered new tools of investigation of insulin resistance in PWS. OBJECTIVE: The purpose of this study was to measure serum resistin and mRNA in adipose tissue of patients with PWS, those with simple obesity, and healthy controls and correlate resistin levels with anthropometric and biochemical features. DESIGN: Twenty-eight adult PWS patients, 29 obese patients, and 25 healthy controls were studied. Anthropometric variables were measured and fasting serum and plasma were collected for measurement of resistin, adiponectin, leptin, lipid profile, glucose, and insulin. RESULTS: Serum resistin and resistin mRNA expression in adipose tissue was significantly higher in PWS patients, compared with both healthy lean controls and obese patients. Moreover, on regression analysis resistin was significantly correlated with body mass index, whereas no significant association was found between resistin and homeostasis model assessment index. A weak association between resistin and adiponectin was found in the PWS group only. However, on multivariate analysis only the correlation between resistin and body mass index remained significant. CONCLUSIONS: These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.     

The metabolic syndrome and high C-reactive protein: prevalence and differences by sex in a southern-European population-based cohort

BACKGROUND: To evaluate the prevalence of the metabolic syndrome (MS) and its components in a population-based cohort, and to analyse the association between gender, environmental conditions, C-reactive protein (CRP), and the syndrome. METHODS: Out of 1877 subjects aged 45-64, who represented all the patients of six family physicians, representative of the sanitary districts of Asti (north-western Italy), 88% accepted to participate in an interview on personal habits, and several clinical and laboratory measurements. RESULTS: The MS (National Cholesterol Education Program criteria) was present in 24% of males and 22% of females. Males had a significantly higher percentage of hyperglycaemia, hypertension, hypertriglyceridemia, whereas females had a higher prevalence of central obesity and low HDL-cholesterol. In a multiple logistic regression model, the MS was significantly associated with increasing age, BMI, and >30 g/day alcohol intake (OR = 1.42; 95% CI 1.27-1.58), and negatively to higher education level (OR = 0.52; 95% CI 0.28-0.99) and moderate exercise (OR = 0.65; 95% CI 0.57-0.76). CRP levels are highly correlated to BMI and the components of the syndrome. The association between CRP and the MS remains significant in women only, in a multivariate analysis, after multiple adjustments (OR = 1.73; 95% CI 1.42-2.11). Higher CRP levels, correlated to smoking and, inversely, to alcohol intake, identify a further 12% of the cohort at higher cardiovascular risk. CONCLUSIONS: The MS affects more than 20% of this middle-aged cohort, but more than 30%, with higher CRP levels are at high cardiovascular risk. Healthier lifestyle habits are inversely associated with the MS and CRP levels, suggesting the need for strategies and their implementation in the general population.     

Ambulatory hypercholesterolemia management in patients with atherosclerosis

OBJECTIVE: To determine whether outpatient cholesterol management varies by gender or race among patients with atherosclerosis, and assess factors related to subsequent cholesterol control. DESIGN: Retrospective cohort study. SETTING: Primary care clinics affiliated with an academic medical center. PARTICIPANTS: Two hundred forty-three patients with coronary heart disease, cerebrovascular disease, or peripheral vascular disease and low-density lipoprotein cholesterol (LDL-C)>130 mg/dl. MEASUREMENTS AND MAIN RESULTS: The primary process of care assessed for 1,082 office visits was cholesterol management (medication intensification or LDL-C monitoring). Cholesterol management occurred at 31.2% of women's and 38.5% of men's visits (P=.01), and 37.3% of black and 31.7% of white patients' visits (P=.09). Independent predictors of cholesterol management included female gender (adjusted risk ratio [ARR], 0.77; 95% confidence interval [CI], 0.60 to 0.97), seeing a primary care clinician other than the patient's primary care physician (ARR, 0.23; 95% CI, 0.11 to 0.45), and having a new clinical problem addressed (ARR, 0.60; 95% CI, 0.48 to 0.74). After 1 year, LDL-C <130 mg/dl occurred less often for women than men (41% vs 61%; P=.003), black than white patients (39% vs 58%; P=.01), and patients with only Medicare insurance than with commercial insurance (37% vs 58%; P=.008). Adjustment for clinical characteristics and management attenuated the relationship between achieving an LDL-C <130 mg/dl and gender. CONCLUSIONS: In this high-risk population with uncontrolled cholesterol, cholesterol management was less intensive for women than men but similar for black and white patients. Less intense cholesterol management accounted for some of the disparity in cholesterol control between women and men but not between black and white patients.