Endothelial Vascular Function in Hypertensive Patients After Renin—Angiotensin System Blockad

It is unclear whether single and combined pharmacologic inhibition of the renin-angiotensin-aldosterone system have similar effects on endothelial function and blood pressure (BP). The authors evaluated 63 hypertensive patients divided into 4 groups (hydrochlorothiazide 25 mg/d; irbesartan [IRBE] 150 mg/d; quinapril [QUIN] 20 mg/d; or IRBE 150 mg/d + QUIN 20 mg/d) and 25 healthy normotensive subjects (normal) followed for 12 weeks. Endothelium-dependent dysfunction measured as flow-mediated dilation at Weeks 0 and 12 were: normal, 11.5%±2.4% vs 13.5%±2.0%; hydrochlorothiazide, 7.3%±2.0% vs 12.8%±3.1%; QUIN, 7.2%±2.8% vs 13.2%±2.1%; IRBE, 7.1%±2.8% vs 13.0%±2.9%; and IRBE + QUIN, 7.5%±1.9% vs 12.8%±3.0%. Nitroglycerin-mediated responses were: normal, 26.0%±1.9% vs 24.0%±2.5%; hydrochlorothiazide, 17.0%±2.2% vs 18.3%±2.6%; QUIN, 17.8%±3.2% vs 23.4%±3.0%; IRBE, 16.8%±3.6% vs 24.7%±2.0%; and IRBE + QUIN, 17.3%±3.0% vs 25.1%±2.5%. Antihypertensive therapy restored BP to normal and improved the endothelium-dependent and -independent dysfunction after renin-angiotensin-aldosterone system blockade. In a further finding, the combined effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade was not superior to the action of either of these treatments separately.     

Usefulness of myocardial contrast echocardiography early after acute myocardial infarction

OBJECTIVES: (1) Evaluate wall motion and perfusion abnormalities after reperfusion therapy of the culprit lesion, (2) delineate the ability of myocardial contrast echocardiography (MCE) to evaluate the microvasculature after reperfusion, in order to distinguish between stunning and necrosis in the risk area. METHODS: We analyzed 446 segments from 28 patients, 10 normal controls (160 segments), and 18 with a first AMI (286 segments). MCE was obtained with Optison and a two-dimensional echocardiography was performed at 3 months post acute myocardial infarction (AMI). RESULTS: In the group with AMI, we analyzed 286 segments, of which 107 had wall motion abnormalities (WMA) related to the culprit artery. Two subgroups were identified: Group I with WMA and normal perfusion (50 segments, 47%) and Group II with WMA and perfusion defects (57 segments, 53%). According to the 2D echocardiogram at 3 months, they were further subdivided into: Group IA: with wall motion improvement (stunning): 18 segments, 36%, Group IB: without wall motion improvement: 32 segments, 64%, Group IIA: with wall motion improvement: 12 segments, 21%, Group IIB: without wall motion improvement (necrosis): 45 segments, 79%. CONCLUSIONS: (1) The presence of myocardial perfusion in segments with WMA immediately after AMI reperfusion therapy predicts viability in most patients. Conversely, the lack of perfusion is not an absolute indicator of the presence of necrosis. (2) Perfusion defects allow to detect patients with thrombolysis in myocardial infarction (TIMI) 3 flow and "no-reflow" phenomenon who will not show improved wall motion in the 2D echocardiogram. However, some patients with initial no-reflow could have microvascular stunning and their regional contractile function will normalize after a recovery period.     

Large-volume leukapheresis for peripheral blood progenitor cell collection in low body weight pediatric patients: a single center experience.

Peripheral blood progenitor cells (PBPC) have became the preferred source of stem cells for autologous transplantation because of easier accessibility, rapid engraftment, and lower tumor cell contamination. In pediatric patients is very important to optimize peripheral blood stem cells (PBSC) harvesting to obtain a sufficient number of cells with a reduced number of leukapheresis. In this study we prospectively analyzed data on 43 large volume leukapheresis (LVL) from 20 consecutive low body weight pediatric patients with various malignancies. Patients' mean body weight was 16.6 kg (range, 8.9-32.0 kg), and the median age was 4 years (range, 1-10 y ears). Instead of saline, it was used irradiated and leukoreduced red blood cell (RBC) units to prime the machine in 15 patients weighting 25 kg or less. The median number of LVL was 2 (range, 1-4) and a mean of 5.2 patient's blood volume was processed per session lasting 165 min (range, 118-239). The mean number of CD34+ cells, one day before leukapheresis was 49 mm(-3) (range, 9-219). The PBPC collection yielded 24.7 x 10(8) total nucleated cells/kg (range, 6.2-74.0), 10.7 x 10(6) kg(-1) CD34+ cells (range, 3.6-53.7); 49.8 x 10(4) CFU-GM/kg (range, 6.4-198.1), and 65.6 x 10(4) BFU-E/kg (range, 7.6-198.1). The platelet count decreased significantly after each procedure 39.8 +/- 9.1 x 10(9) mm(-3) (range, 18.000-76.000) (p < 0.001). In conclusion, our data show that LVL for collection of PBPC in low weight pediatric patients is a safe and efficient procedure, but it may expose the patient to the risk of thrombocytopenia.     

Complications of circumferential pulmonary vein isolation using the cryoballoon technique: Incidence and predictors

Background

Cryoballoon ablation technique for the treatment of atrial fibrillation (AF) is a complex procedure consisting of several procedural steps associated with significant risk of complications. The aim of this single-centre study was to give detailed analysis of the complication rate and corresponding risk factors of pulmonary veins cryoisolation (PVI) procedures.

Methods and results

A total of 158 consecutive patients (71.5% men, aged 57 ± 9 years, 73.3% paroxysmal atrial fibrillation) were enrolled. Out of 632 pulmonary veins, 96.7% were targeted and isolated by 2–7 applications of cryothermal energy guided with intracardiac echocardiography and fluoroscopy. The additional ablation of cavotricuspid isthmus was performed in 14.6% of procedures. In total, 29 complications were recorded in peri-procedural or early post-procedural period, 8 (5.1%) of them being evaluated as major. No case of permanent injury, disability or death was registered. Multivariate logistic regression showed the persistence of pre-ablation AF as the risk factor of major complications (OR = 5.0; ± 95% CI: 1.14–21.97, P = 0.033); lower body height was the significant risk factor of any complications (OR = 0.95; ± 95% CI: 0.91–0.99, P = 0.026) with rapid increase of complication risk with body height ≤ 162 cm. Embolic complications were significantly associated with the pre-ablation AF, while patients with low body height had a trend towards increased risk of phrenic nerve palsy.

Conclusion

Our study confirmed that the cryoballoon pulmonary vein isolation can be safely performed with low incidence of life-threatening complications which may be further decreased if the mentioned risk factors are handled appropriately.     

Prevalence rate of urinary incontinence in community-dwelling elderly individuals: the Veneto study

BACKGROUND: Urinary incontinence (UI) is a common problem in elderly people, due mainly to functional impairments and concurrent medical diseases. Few studies, however, have assessed the prevalence of UI in noninstitutionalized individuals. The objectives of the present work were to estimate the prevalence of UI in a community-based population of elderly Italians and to determine the associated physical, social, and psychological factors. METHODS: A random sample of noninstitutionalized men (n = 867) and women (n = 1531), aged 65 years and older, from the Veneto region of northeastern Italy, were interviewed at home, using an extensive multidisciplinary questionnaire, to assess their quality of life and social, biological, and psychological correlates. RESULTS: The prevalence rate of UI was of 11.2% among men and of 21.6% among women. Among those reporting the condition, approximately 53% of women and 59% of men reported experiencing incontinence daily or weekly. Association of UI was found for participants older than 70 years in both men (odds ratio [OR] 2.49, 95% confidence interval [CI] 1.45-4.28) and women (OR 1.49, 95% CI 1.11-2.02). Three of the medical conditions investigated were associated with increases in the odds in women, namely chronic obstructive pulmonary disease (OR 1.53, 95% CI 1.11-2.12), Parkinsonism (OR 2.27, 95% CI 1.14-4.54), and hip fracture (OR 1.38,95% CI 1.02-1.88), whereas chronic diarrhea was the only condition associated with UI in men (OR 6.92, 95% CI 2.22-21.5). Participants with a physical disability were two times more likely to report incontinence, and the odds were increased by 50% in women who had sleep disturbances. CONCLUSIONS: Incontinence is highly prevalent in the Italian elderly population, and several common chronic conditions are significantly associated with it. Moreover, very few people with incontinence seek health care or are aware of potential treatments.     

BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)-induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3-only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector-mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal-regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim(-/-) mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.     

Enzyme replacement therapy on hypophosphatasia mouse model

Hypophosphatasia (HPP) is an inborn error of metabolism caused by deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP), resulting in a defect of bone mineralization. Natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5-phosphate (PLP), a co-factor form of vitamin B6. Enzyme replacement therapy (ERT) for HPP by functional TNSALP is one of the therapeutic options. The C-terminal-anchorless human recombinant TNSALP derived from Chinese hamster ovary cell lines was purified. TNSALP-null mice (Akp2 ^-/- ), an infantile model of HPP, were treated from birth using TNSALP and vitamin B6 diet. Long-term efficacy studies of ERT consisted of every 3 days subcutaneous or intravenous injections till 28 days old (dose 20 U/g) and subsequently every 3 days intravenous injections for 6 months (dose 10 U/g). We assessed therapeutic effect by growth and survival rates, fertility, skeletal manifestations, and radiographic and pathological finding. Treated Akp2 ^-/- mice grew normally till 4 weeks and appeared well with a minimum skeletal abnormality as well as absence of epilepsy, compared with untreated mice which died by 3 weeks old. The prognosis of TNSALP-treated Akp2 ^-/- mice was improved substantially: 1) prolonged life span over 6 months, 2) improvement of the growth, and 3) normal fertility. After 6 months of treatment, we found moderate hypomineralization with abnormal proliferative chondrocytes in growth plate and articular cartilage. In conclusion, ERT with human native TNSALP improves substantial clinical manifestations in Akp2 ^-/- mice, suggesting that ERT with anchorless TNSALP is also a potential therapy for HPP.     

Administration of live varicella vaccine to HIV-infected children with current or past significant depression of CD4(+) T cells

BACKGROUND: Varicella can be a severe illness in human immunodeficiency virus (HIV)-infected children. The licensed, live attenuated varicella vaccine is safe and immunogenic in HIV-infected children with minimal symptoms and good preservation of CD4(+) T cells (Centers for Disease Control and Prevention immunologic category 1). METHODS: To study the safety and immunogenicity of this vaccine in varicella-zoster virus (VZV)-naive, HIV-infected children with moderate symptoms and/or more pronounced past or current decreases in CD4(+) T cell counts, such children (age, 1-8 years) received 2 doses of vaccine 3 months apart. The children were observed in a structured fashion for adverse events. Blood was tested for VZV antibody and VZV-specific cell-mediated immunity (CMI) at baseline, 8 weeks after each dose, and annually for 3 years. Subjects who had no evidence of immunity 1 year after vaccination received a third dose and were retested. RESULTS: The vaccine was well tolerated; there were no vaccine-related, serious adverse events. Regardless of immunologic category, at least 79% of HIV-infected vaccine recipients developed VZV-specific antibody and/or CMI 2 months after 2 doses of vaccine, and 83% were responders 1 year after vaccination. CONCLUSIONS: HIV-infected children with a CD4(+) T cell percentage of > or =15% and a CD4(+) T cell count of > or =200 cells/ microL are likely to benefit from receiving varicella vaccine.     

Anti-beta2-glycoprotein I: prevalence, clinical correlations, and importance of persistent positivity in patients with antiphospholipid syndrome and systemic lupus erythematosus

OBJECTIVE: Antibodies to beta2-glycoprotein I (anti-beta2-GPI) are found in a large percentage of patients with primary or secondary antiphospholipid syndrome (APS). Our aim was to identify the prevalence and clinical correlation of these antibodies in patients with APS and systemic lupus erythematosus (SLE), in comparison to anticardiolipin (aCL) and the lupus anticoagulant (LAC). We investigated whether serial samples improve clinical utility. METHODS: Serum samples for anti-beta2-GPI (IgG, IgM, IgA), aCL (IgG, IgM, IgA), and LAC (by dilute Russell viper venom time; RVVT) were collected from 418 consecutive patients with SLE or APS between October 2002 and March 2003. Clinical and serologic data of these patients were analyzed. RESULTS: A total of 185 (44.5%) patients were positive for anti-beta2-GPI, 55.3% were positive for aCL, and 31.1% for LAC. Anti-beta2-GPI was more common in Caucasians than in African Americans (p = 0.098). IgM and IgA were the most frequent isotypes of anti-beta2-GPI. aCL and anti-beta2-GPI were highly associated (p < 0.0001 to p = 0.0177, depending on isotype). A positive association was found between the presence of the LAC by dilute RVVT and anti-beta2-GPI IgG (p < 0.0001), IgM (p < 0.0001), and IgA (p = 0.0002) antibodies. Persistent positivity increased the association of venous and arterial thrombosis with anti-beta2-GPI (IgG and IgM isotypes). Pregnancy loss, seizures, and migraines were not associated with anti-beta2-GPI. IgA anti-beta2-GPI was not significantly associated with any manifestation of APS. CONCLUSION: The prevalence of anti-beta2-GPI IgM and IgA was very high in our population. Measurement of anti-beta2-GPI IgG is clinically useful in identifying patients with SLE at higher risk for venous and arterial thrombosis. Persistent positivity increased the association of IgG anti-beta2-GPI with venous thrombosis and anti-beta2-GPI IgM with arterial thrombosis. IgA anti-beta2-GPI was not significantly associated with APS manifestations.     

IL-1 resets glucose homeostasis at central levels

Administration of IL-1beta results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1beta gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db/db mice; (iii) IL-1-treated normal and db/db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1beta expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory/immune processes.