Adiponectin in outpatients with coronary artery disease: independent predictors and relationship with heart failure.

BACKGROUND AND AIMS: Chronic heart failure (HF) is characterised by a neurohormonal dysfunction associated with chronic inflammation. A role of metabolic derangement in the pathophysiology of HF has been recently reported. Adiponectin, an adipose-tissue-derived cytokine, seems to play an important role in cardiac dysfunction. We investigated the variation of circulating adiponectin in patients with coronary artery disease (CAD), with or without HF, in order to identify its independent predictors. METHODS AND RESULTS: A total of 107 outpatients with CAD were enrolled in the study and divided into three groups: CAD without left ventricular systolic dysfunction (group 1); CAD with left ventricular dysfunction without HF symptoms (group 2) and CAD with overt HF (group 3). Plasma adiponectin was determined by enzyme-linked immunosorbent assay. Adiponectin concentrations increased progressively from group 1 (7.6 ± 3.6 ng ml⁻¹) to group 2 (9.1 ± 6.7 ng ml⁻¹) and group 3 (13.7 ± 7.6 ng ml⁻¹), with the difference reaching statistical significance in group 3 versus 1 and 2 (p < 0.001). A multivariable model of analysis demonstrated that the best predictors of plasma adiponectin were body mass index, N-terminal pro-brain natriuretic peptide and high-density lipoprotein cholesterol. However, even after adjusting for all three independent predictors, the increase of adiponectin in group 3 still remained statistically significant (p = 0.015). CONCLUSION: Our data confirm the rise of adiponectin in overt HF. The levels of circulating adipokine seem to be mainly predicted by the metabolic profile of patients and by biohumoral indicators, rather than by clinical and echocardiographic indexes of HF severity.

Effects of hemoperfusion with an immobilized polymyxin-B fiber column on cytokine plasma levels in patients with abdominal sepsis.

AIM: The beneficial role of hemofiltration with immobilized polymyxin-B fiber (PMX) columns in sepsis, especially sepsis due to gram-negative bacteria, has previously been emphasized. Although the efficacy of PMX-B fiber-mediated hemofiltration in reducing plasma levels of cytokines has been reported, other studies did not confirm this observation. Here we report the effects of PMX-B fiber-mediated hemofiltration on outcome and cytokine plasma levels in patients with abdominal sepsis. METHODS: Twelve consecutive patients admitted to the Intensive Care Unit (October 2006-December 2007) for severe sepsis/septic shock from abdominal infection were treated with standard therapy and 2 cycles of hemofiltration with PMX cartridges. Clinical data and plasma levels of IL-6, IL-10 and TNF-a were measured 24 hours before and after PMX treatment. RESULTS: Plasma concentrations (pg/mL) of IL-6, IL-10 and TNF-a were significantly lower after hemofiltration with a PMX fiber column (279.9+/-69.2 vs. 130.9+/-18.4, 166.4+/-36.7 vs. 45.5+/-12.2, 83.1+/-13.5 vs. 23.9+/-5.1 pg/mL, respectively; P<0.05). After treatment, patients required lower doses of norepinephrine (0.3+/-0.1 vs. 0.8+/-0.1 mg/kg/min) and reduced lactate levels, recovery of respiratory function and improved Simplified Organ Failure Assessment (SOFA) scores. After 28 days, 6 patients (50%) had survived. Subgroup analysis demonstrated that survivors had higher IL-6 and lower IL-10 and TNF-a pre-treatment plasma levels (pg/mL) compared with deceased patients (324.4+/-41.1 vs.235.3+/-38.4; 98.5+/-16.1 vs. 234.3+/-48.6, 44.5+/-9.0 vs.121.6+/-52.3 pg/mL, respectively; P<0.05). No adverse events imputable to the treatment were recorded. CONCLUSION: Hemofiltration with a PMX fiber column was able to reduce plasma levels of IL-6, IL-10 and TNF-a, especially in patients surviving at 28 days. Use of the technique was associated with lower norepinephrine support and an increased PaO2/FiO2 ratio.

Inmunoterapia específica para enfermedades alérgicas respiratorias: estado de la cuestión de acuerdo a los metanálisis actuales / Specific inmunotherapy for respiratory allergy: state of the art according to current meta-analyses

Objetivos: evaluar la eficacia de la inmunoterapia alergeno especifica (IT)en el tratamiento del asma y la rinitis alérgica de niños y adultos, mediante el examen de diferentes metanálisis (MTA) realizados hasta la actualidad.

Effectiveness of omalizumab in a patient with severe asthma and atopic dermatitis.

The anti-IgE antibody omalizumab is currently indicated in severe asthma not controlled by standard drug therapy. Recently, new indications for omalizumab were suggested, which include atopic dermatitis (AD), a skin disorder characterized by elevated levels of IgE. We report the case of a 39-year old woman with severe asthma and severe AD, both resistant to conventional drug treatment. The patient had a IgE level of 1304 kU/L, which exceeded the recommended maximum level for treating asthma with omalizumab (stated in 700 Ku/L) but was far lower than previously reported in cases of AD treated with anti-IgE. The treatment consisted of a dose of omalizumab 375 mg every two weeks, and induced a rapid improvement of asthma, with no need of other drugs after three months, along with a progressive decline of severity of AD, which after five months was completely cured. These findings suggest the usefulness of omalizumab in patients with concomitant severe asthma and AD, also considering the pharmaco-economic balance obtained by withdrawing the multiple drugs used to treat both diseases.

Efficacy of mometasone furoate nasal spray in the treatment of allergic rhinitis. Meta-analysis of randomized, double-blind, placebo-controlled, clinical trials.

RATIONALE: Several randomized, double-blind, placebo-controlled clinical trials have demonstrated the efficacy of mometasone furoate nasal spray (MFNS) in the treatment of allergic rhinitis (AR) thus allowing for a meta-analysis to determine the overall treatment effect. METHODS: A comprehensive search of the MEDLINE, LILACS, SCOPUS, and the Cochrane Library databases up to 31 October, 2007 was carried out. Randomized, double-blind, placebo-controlled, clinical trials evaluating the efficacy of MFNS in patients with AR compared to placebo were included. Total nasal symptom scores (TNSS), individual nasal symptoms, total non-nasal symptom scores (TNNSS) and nasal airflow were analysed as the standardized mean difference (SMD). Meta-analysis was performed with the random or the fixed effect models depending on heterogeneity, by using revman 5 software. DATA SYNTHESIS: Sixteen of the 113 identified articles met the inclusion criteria. For MFNS efficacy on TNSS, 2998 participants were analysed: 1534 received MFNS and 1464 placebo. Mometasone furoate nasal spray was associated with a significant reduction in TNSS (SMD -0.49, 95% CI: -0.60 to -0.38; P < 0.00001; I(2) = 50.1%). A significant effect on SMD for nasal stuffiness/congestion (-0.41; 95% CI: -0.56 to -0.27), rhinorrhoea (-0.44; 95% CI: -0.66 to -0.21), sneezing (-0.40; 95% CI: -0.57 to -0.23) and nasal itching (-0.39; 95% CI: -0.53 to -0.25) was also demonstrated. Mometasone furoate nasal spray treated subjects also showed a significant reduction in TNNSS (-0.30; 95% CI: -0.43 to -0.18). The proportion of patients with adverse events was similar for MFNS and placebo (0.99; 95% CI: 0.81-1.20; P = 0.91). CONCLUSIONS: This meta-analysis provides a level Ia evidence for the efficacy of MFSN in the treatment of AR vs placebo. Adverse events frequency was similar in both groups.

The impact of GINA suggested drugs for the treatment of asthma on Health-Related Quality of Life: a GA(2)LEN review.

Asthma represents a serious global health problem. People of all ages in countries throughout the world are affected by this chronic airway disorder that, when uncontrolled, can place severe limits on daily life and can even be fatal. Asthma cannot be removed, but asthmatic symptoms can be cured; as for many other chronic diseases, pharmacotherapy is important to reduce the risk of asthma-related mortality, decrease disability and improve symptoms and quality of life. The action of antiasthmatic drugs directly contributes to decrease symptoms severity, improve spirometric results, reduce airway hyperresponsiveness and prevent irreversible airway remodelling. Antiasthmatic therapy is necessary for long-term control of asthma symptoms. Asthma and antiasthmatic drugs can influence patient's quality of life: this is why healthcare systems have recently focused on research studies about Health-Related Quality of Life (HRQL) in asthmatic patients. Numerous validated questionnaires are available and many studies have been performed evaluating HRQL in people affected by asthma, thus testifying a great interest in this topic. The aims of the present review are to examine the scientific literature of the last 4 years (January 2004-December 2007) dealing with the impact of asthma treatments suggested by Global Initiative for Asthma guidelines on patients' quality of life, and to identify the unexplored or not fully investigated areas concerning this issue.

ARIA-suggested drugs for allergic rhinitis: what impact on quality of life? A GA2LEN review.

Allergic diseases constitute a global health problem, as they have an increasing economic and social impact and, especially, they can deeply interfere with the patients' daily life, being a cause of physical and emotional discomfort. This is why the health-related quality-of-life (HRQoL) has become increasingly important in health care research; in fact, the assessment of the impact the disease and its treatment have on patients, provides a more comprehensive approach in outcome evaluation. Numerous validated questionnaires are available and many studies have been performed evaluating HRQoL in people affected by allergic rhinitis (AR), thus testifying a great interest in this topic. The aims of the present review are: to examine the scientific literature of the last 3 years dealing with the impact of AR treatments suggested by allergic rhinitis and its impact on asthma guidelines on patients' QoL, and to identify the unexplored or not-fully-investigated areas concerning this issue.

Severe hyponatremia due to hypopituitarism with adrenal insufficiency: a case report.

OBJECTIVE: Adrenal insufficiency due to hypopituitarism can lead to severe hyponatremia with potentially fatal consequences. Prompt diagnosis and adequate hormonal replacement therapy are essential to block an otherwise unfavorable course and to re-establish a healthy life. Unfortunately, this condition is often misdiagnosed. DESIGN: Case report. SETTING: Intensive Care Unit of a teaching hospital. PATIENT: A 76-yr-old man with refractory hypotension, acute myocardial infarction, and left ventricular dysfunction, secondary to severe chronic pan-hypopituitarism, associated with severe hyponatremia. METHODS AND MAIN RESULTS: The patient underwent mechanical ventilation and continuous venous-venous hemodiafiltration, for severe respiratory and renal insufficiency. A hormonal replacement therapy with T4, hydrocortisone, and nandrolone was started and the patient was discharged to a rehabilitation facility after 31 days of hospitalization. CONCLUSIONS: Hypopituitarism with secondary adrenal insufficiency is often misdiagnosed at an early stage and a high degree of suspicion is necessary for early diagnosis. Determination of plasma cortisol level in patients with hyponatremia not explained by other causes should always be obtained.

Analysis of protease-activated receptor-1 and -2 in human scar formation.

Protease-activated receptor (PAR)-1 and PAR-2 are reported to contribute to the fibrotic process in a number of organs, including lung, liver, pancreas, and kidney. The aim of this study was to localize expression and biological activity of PAR-1 and PAR-2 in normal and pathological cutaneous scars. First, we investigated the immunohistochemical expression of PAR-1 and PAR-2 proteins in a series of human normal scars (NS, n = 10), hypertrophic scars (HS, n = 10), and keloids (K, n = 10). Expression of PAR-1 and PAR-2 was observed in all types of scar. Specifically, in HS and K, diffuse PAR-1 and PAR-2 positivity was found in dermal cellular areas composed of myofibroblasts, while no or minor staining was observed in the scattered fibroblasts embedded in abundant extracellular matrix in the context of the more collagenous nodules, irrespective of the type of scar. The hyperplastic epidermis overlying K was also found to be strongly PAR-1 and PAR-2 positive, whilst in most NS and HS the epidermis was faintly to moderately stained. Second, ribonuclease protection assay on paraffin-embedded specimens showed overexpression of PAR-1 and PAR-2 mRNA in K compared to NS and HS. Third, cultured human fibroblasts exposed to TGF-beta1 expressed a myofibroblast phenotype associated with overexpression of PAR-2, while PAR-1 expression was unaffected. Intracellular Ca(2+) mobilization by PAR-2 agonists in myofibroblasts was increased as compared to fibroblasts, whereas the effect of PAR-1 agonists was unchanged. Our in vivo study indicates that PAR-1 and PAR-2 are expressed in cells involved in physiological and pathological scar formation and suggests that in vitro overexpression and exaggerated functional response of PAR-2 may play a role in the function of myofibroblasts in scar evolution from a physiological repair process to a pathological tissue response.

Expression of protease-activated receptor-1 and -2 in orofacial granulomatosis.

OBJECTIVE: Orofacial granulomatosis (OFG) is a rare condition characterized by non-caseating granulomas in the orofacial region. Protease-Activated Receptors (PARs) play a role in inflammatory diseases in diverse human tissues. The aim of the study was to investigate the expression of PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 in tissues taken from OFG patients. METHODS: PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn's disease (five cases), Melkersson-Rosenthal syndrome (MRS) (six cases), cheilitis granulomatosa (five cases) and normal oral mucosa (five cases). RESULTS: PAR-1 was observed in mononuclear inflammatory cells in edematous/lichenoid lesions, whereas a strong PAR-2 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions, irrespective of the clinical features (Crohn vs MRS). MMPs and COX-2 were expressed in the inflammatory component of edematous/lichenoid lesions and markedly overexpressed in granulomatous lesions. COX-1 was weakly and variably expressed in both edematous/lichenoid and granulomatous lesions. CONCLUSION: Thus, PAR-1 and PAR-2 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion. Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes.

Asthma treatment: 'magic bullets which seek their own targets'.

The most fascinating options of the new asthma treatments are probably represented by monoclonal antibodies. In fact, these molecules are virtually able to interact with whatever specific antigen. Anyway, it is mandatory to understand the limits of this group of molecules, in terms of both efficacy and safety. In this review, we have analyzed different ways of interfering along the course of the cascade of the allergic reaction, targeting different molecules (CD4, TNF-alpha, IL-4, IL-5, IL-10, IL-12, endothelial adhesion molecules, IgE), showing the efficacy and the risks of each kind of treatment. In the end, we focused our attention on omalizumab, the monoclonal antibody targeting IgE. Although with some restrictions, represented by the high costs and the limitation of its use only to a specific subset of patients affected by allergic asthma, at present anti-IgE appear to be the only 'magic bullet' for the treatment of allergic asthma. In fact, it proved to reduce exacerbations and symptom scores, and to improve quality of life, with a very good safety profile.

Efficacy of desloratadine in the treatment of allergic rhinitis: a meta-analysis of randomized, double-blind, controlled trials.

The objective of the study is to assess the efficacy of the nonsedating antihistamine, desloratadine, in the treatment of allergic rhinitis (AR). A search of MEDLINE, EMBASE, LILACS, and CINAHL databases was undertaken from January, 1966 to May, 2006. Double-blind, randomized, controlled studies of desloratadine in the treatment of AR in adult patients were carried out. The measured outcomes included the total symptoms score, the total nasal symptoms score, nasal airflow, and inflammatory markers (nasal eosinophils, nasal interleukin-4). The analysis included the calculation of standardized mean difference (SMD). A total of 57 studies were analyzed, and 13 randomized, double-blind, controlled trials were included in the meta-analysis. The trials included 3108 subjects who had completed studies involving desloratadine. There was significant heterogeneity among the study results, because of differing study methodologies. Desloratadine was associated with significant reductions in total symptoms scores (SMD -1.63; 95% CI -2.75 to -0.51; P = 0.004) and total nasal symptoms score (SMD -0.66; 95% CI -0.91 to -0.42; P < 0.001), when compared with placebo. Analysis of objective data on nasal blockage demonstrated a significant improvement in nasal airflow with desloratadine, when compared with placebo (SMD 0.32; 95% CI 0.10 to 0.55; P = 0.005). A benefit favoring desloratadine over placebo in terms of nasal eosinophil levels was also noted in the analysis. This meta-analysis confirms the reduction of AR symptoms and improvement in nasal airflow seen in individual studies of desloratadine. Objective improvements in nasal airflow, total symptoms, and total nasal symptoms seen with desloratadine are supported by Ia evidence.

Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory recurrent infections.

Respiratory tract infections (RTIs) represent a serious problem because they are one of the most common cause of human death by infection. The search for the treatment of those diseases has therefore a great importance. In this study we provide an overview of the currently available treatments for RTIs with particular attention to chronic obstructive pulmonary diseases exacerbations and recurrent respiratory infections therapy and a description of bacterial lysate action, in particular making reference to the medical literature dealing with its clinical efficacy. Those studies are based on a very large number of clinical trials aimed to evaluate the effects of this drug in maintaining the immune system in a state of alert, and in increasing the defences against microbial infections. From this analysis it comes out that bacterial lysates have a protective effect, which induce a significant reduction of the symptoms related to respiratory infections. Those results could be very interesting also from an economic point of view, because they envisage a reduction in the number of acute exacerbations and a shorter duration of hospitalization. The use of bacterial lysate could therefore represent an important means to achieve an extension of life duration in patients affected by respiratory diseases.

Chronic cough and QoL in allergic and respiratory diseases measured by a new specific validated tool-CCIQ.

Even though chronic cough (CC) is a bothersome symptom, only a small number of studies have evaluated its specific burden on health-related quality of life (HRQL). The aim of the present study was to assess how the presence of CC interferes with HRQL. A total of 95 outpatients were enrolled during medical consultation at our "Chronic Cough Center". A health status measure (SF-36) and a new HRQL questionnaire specific for CC (CCIQ) were administered before the initial visit. Compared to the reference sample, CC patients reported significantly lower scores in 5 of 8 SF-36 domains: Social functioning (t=10.292), Physical role limitation (t=9.667), Emotional role limitation (t=7.712), General health (t=5.154) and Vitality (t=4.426). The analysis of CCIQ scores showed a disability due to CC, independent of its etiology. The greatest disabilities were observed in the Social relationship (58.33) domain, followed by Sleep/Concentration (54.26), Mood (51.49) and Daily activities (47.69). Sleep, disturbing the partner, and irritability were the three outstanding aspects, affecting 80% of patients. These results show that CC has a high negative impact on HRQL, and they further suggest that the CCIQ is a useful tool for obtaining a global evaluation including its impact and therapeutic options.

A new tool to assess and monitor the burden of chronic cough on quality of life: Chronic Cough Impact Questionnaire.

INTRODUCTION: Chronic cough, one of the most frequent causes for a patient to consult a medical practitioner, limits the course of normal activities in everyday life of the patient affected (work, physical activities, social relations, night sleep). By now, there are few validated questionnaires for the evaluation of the impact of this symptom in the patient's quality of life (QoL). For this reason, we created a new questionnaire for the assessment of QoL in patients affected by chronic cough (Chronic Cough Impact Questionnaire, CCIQ). MATERIALS AND METHODS: In the development procedure of CCIQ an initial questionnaire of 40 items was compiled and given to a first pool of 170 patients, each coming to our attention because of chronic cough; then the 25 most significant items were detected and converted into questions evaluating the answers on a Likert scale of five steps. Consequently, this final questionnaire underwent a validation procedure to assess its construct validity, internal consistency, reliability, and responsiveness. 95 patients (44.2% F, 55.8% M) were evaluated (age 53.69 +/- 11.7 years). RESULTS: Following a statistical analysis, CCIQ showed a four-dimensional structure and good levels of internal consistency for the extracted factors: sleep/concentration (79.98), relationship (86.98), daily life impact (69.04), and mood (65.41). In stable conditions CCIQ showed a good reliability, ranged between 0.67 and 0.88. Responsiveness to clinical changes was accomplished. DISCUSSION: These results provide evidence that CCIQ has specificity enough for being a valid tool for detecting the relative burden of cough on subjective well-being, and for obtaining a global evaluation both of chronic cough impact and of treatments for it, taking into account the patient's point of view. The CCIQ was easily and quickly filled in by the patients while waiting, and it was accepted by the patients.

Isolated ambulatory hypertension is common in outpatients referred to a hypertension centre.

The present investigation was aimed at determining the prevalence and the blood pressure (BP) profile of isolated ambulatory hypertension, defined as an elevated ambulatory BP with normal office blood pressure, in a series of 1488 consecutive outpatients referred for routine clinical evaluation of suspected or established arterial hypertension. All patients underwent both office BP (OBP) measurement by a physician and 24-h ambulatory blood pressure monitoring (ABPM). Using OBP values (cutoff for diagnosis of hypertension >/=140/90 mmHg) and daytime ABPM (cutoff for diagnosis of hypertension >/=135/85 mmHg), patients were classified into eight subgroups. In the whole series we found that, independent of treatment status, the prevalence of isolated ambulatory hypertension exceeded 10%. More importantly, 45.3% of individuals who presented with normal OBP values, showed elevated BP at ABPM. Night-time BP, 24-h pulse pressure, and BP variability were significantly higher in isolated ambulatory hypertensives than in normotensive or in white-coat hypertensive individuals. Therefore, isolated ambulatory hypertension is characterized by a blood pressure profile that is similar to that observed in sustained hypertension. These findings suggest that isolated ambulatory hypertension is very common and probably the indications for ABPM should be more extensive in outpatients referred to hypertensive centre.

S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro.

S100A13, a member of the S100 gene family of Ca(2+)-binding proteins has been previously characterized as a component of a brain-derived heparin-binding multiprotein aggregate/complex containing fibroblast growth factor 1 (FGF1). We report that while expression of S100A13 in NIH 3T3 cells results in the constitutive release of S100A13 into the extracellular compartment at 37 degrees C, co-expression of S100A13 with FGF1 represses the constitutive release of S100A13 and enables NIH 3T3 cells to release S100A13 in response to temperature stress. S100A13 release in response to stress occurs with kinetics similar to that observed for the stress-induced release of FGF1, but S100A13 expression is able to reverse the sensitivity of FGF1 release to inhibitors of transcription and translation. The release of FGF1 and S100A13 in response to heat shock results in the solubility of FGF1 at 100% (w/v) ammonium sulfate saturation, and the expression of a S100A13 deletion mutant lacking its novel basic residue-rich domain acts as a dominant negative effector of FGF1 release in vitro. Surprisingly, the expression of S100A13 also results in the stress-induced release of a Cys-free FGF1 mutant, which is normally not released from NIH 3T3 cells in response to heat shock. These data suggest that S100A13 may be a component of the pathway for the release of the signal peptide-less polypeptide, FGF1, and may involve a role for S100A13 in the formation of a noncovalent FGF1 homodimer.

The precursor but not the mature form of IL1alpha blocks the release of FGF1 in response to heat shock.

Interleukin (IL)1alpha mediates proinflammatory events through its extracellular interaction with the IL1 type I receptor. However, IL1alpha does not contain a conventional signal peptide sequence that provides access to the endoplasmic reticulum-Golgi apparatus for secretion. Thus, we have studied the release of the precursor (p) and mature (m) forms of IL1alpha from NIH 3T3 cells. We have demonstrated that mIL1alpha but not pIL1alpha was released in response to heat shock with biochemical and pharmacological properties similar to those reported for the stress-mediated release pathway utilized by fibroblast growth factor (FGF)1. However, unlike the FGF1 release pathway, the IL1alpha release pathway appears to function independently of synaptotagmin (Syt)1 because the expression of a dominant-negative form of Syt1, which represses the release of FGF1, did not inhibit the release of mIL1alpha in response to temperature stress. Interestingly, whereas the expression of both mIL1alpha and FGF1 in NIH 3T3 cells did not impair the stress-induced release of either polypeptide, the expression of both pIL1alpha and FGF1 repressed the release of FGF1 in response to temperature stress. These data suggest that the release of mIL1alpha requires proteolytic processing of its precursor form and that mIL1alpha and FGF1 may utilize similar but distinct mechanisms for export.